Discussion

 

We are going to start with a brief discussion. What are the possible primary and acquired resistance mechanisms in patients with mCRPC? Let us think about this for the 2 of you in context, what are you most excited about? Chuck, we have not heard from you tonight. What do you think, Mr. Bass?

 

Dr Charles Ryan (Genitourinary Oncology Service): Mr. Bass. What am I most excited about in terms of understanding mCRPC?

 

Dr Morgans: Or these acquired resistance mechanisms. What are you thinking about? Then are there any drugs that could potentially overcome some of those?

 

Dr Ryan: I will tell you one of the things I think about a lot is that we need to integrate an understanding of the biology of the disease that we are treating, not just a list of the drugs that we have available. Genomic testing should now be routine in practice where we are assessing it in order to determine if a patient is eligible for a PARP inhibitor or an immunotherapy. However, it does way more than that. It teaches us a lot about the underlying mutational status of the tumor, and thus we can all educate ourselves every day with our patients by getting genomic testing. That is number one.

 

I would say that the other thing I am excited about is the topic that I was given to talk about, which is to me very interesting, which is the cell surface is a whole new opportunity for us to develop new treatments, whether it is radioligand therapies, antibody–drug conjugates, immunotherapies, etc. Of course, we are seeing that revolutionize a number of other cancers as well. We are just learning more and more about this process in prostate cancer. I think that is very exciting.

 

Dr Morgans: That is great. A lot of those proteins are involved in those resistance mechanisms. So wonderful ways to target. Then Neal, anything that you are thinking about in terms of resistance and then possible ways to get around it?

 

Dr Shore: Yes. I will just briefly. I love Chuck's answer, but resistance to AR pathway inhibitors, unfortunately they do not last forever. I think we are going to be presenting tonight some of the really interesting novel MOAs and the trials that are looking to be additive to ARPIs to decrease the onset of resistance. I think that is going to be super important. Of course, that moves more towards all the different ways we can think about combination therapy.

 

Dr Morgans: Absolutely, especially when we are thinking about AR pathway inhibitors, I think we often think about androgen receptor mutations, we can have amplification of that androgen receptor. There are a lot of ways that that can be engaged and really taken advantage of by the cancer cell.

 

[00:42:42]

 

Pretest 1: When speaking with a colleague, how would you describe the primary mechanism of action of mevrometostat?

 

Let us do a pretest question 1. There should be 2 questions here. When speaking with a colleague, how would you describe the primary mechanism of action of mevrometostat? Please take a moment, let us know. Is it..

 

1. An alpha radionuclide targeting EZH2;
2. A bispecific T-cell engager binding to EZH2;
3. A direct inhibitor of EZH2;
4. A novel androgen receptor degrader; or
5. PARP inhibitor.

 

Thank you for entering your answer. We will go on and see. Okay. It looks like most people think that it is a direct inhibitor of EZH2. We will hear about this more in a minute. I think you are right. We will continue that conversation.

 

[00:43:43]

 

Pretest 2: Which of the following patient populations with mCRPC is eligible for enrollment in the ongoing randomized phase III MEVPRO-1 and MEVPRO-2 trials?

 

Which of the following patient populations with mCRPC is eligible for enrollment in the ongoing randomized phase III MEVPRO-1 and MEVPRO-2 trials? Is it patients:

 

1. Previously treated with ADT plus 1 prior line of chemo for mCRPC;
2. Previously treated with ADT and no prior chemo for mCRPC;
3. Treated after 1 prior line of chemo for mCRPC; or
4. Treated after greater than 2 lines of chemotherapy for mCRPC?

 

Let us see what you said. All right. Previously treated with ADT in 1 line of chemo for mCRPC. We are going to discuss. We will go onto the next question, and we will go through some of that information.

 

[00:44:36]

 

Clinical Course of Prostate Cancer

I think just to remind us all of the clinical course for prostate cancer, we know that on the left-hand side of the slide we see that a majority of patients are actually diagnosed with localized disease or locally advanced disease and then undergo definitive therapy. They can have relapse after that definitive therapy that can either be metastatic disease, and we would characterize that typically as metastatic hormone-sensitive prostate cancer, or they might have a biochemical recurrence and develop nonmetastatic hormone-sensitive prostate cancer, previously just called biochemical recurrence.

 

Patients given ADT can develop progressive disease, they can have nmCRPC or nonmetastatic CRPC, or can develop overt metastatic CRPC. Certainly, patients can come in with de novo metastatic disease, though that is less common and have that progression to mCRPC after initial treatment. However, ultimately, mCRPC is the incurable form of advanced prostate cancer that we really need to ensure we have treatments to address.

 

[00:45:39]

 

Treatment Options Across Prostate Cancer Disease States

 

There are many treatment options already available across the disease states for prostate cancer. Certainly, in the localized setting we have radiation and surgery as options, and then ADT as well as enzalutamide for biochemical recurrent disease. Then, when we get into the hormone-sensitive and mCRPC settings, we have many systemic therapies including things like androgen receptor pathway inhibitors as well as chemotherapies, immunotherapies, targeted therapies like PARP inhibitors and others.

 

[00:46:07]

 

mCRPC: Unmet Needs and Current Status

 

There are still unmet needs in terms of this disease remaining incurable, and we do need to make sure that we address that with ongoing therapeutic advances. Also, importantly, we do know that there are differences in prognosis by metastatic site and that is what the figure on the right shows that patients who have lymph node only metastasis have a longer overall survival than say a patient with liver metastasis, which we know has the poorest prognosis. As we are counseling patients and thinking about therapeutic choices, we often take these into consideration as well as the pace of disease progression.

 

[00:46:41]

 

Optimizing Germline and Somatic Testing for mCRPC Is a Significant Unmet Need

 

We did hear that germline and somatic testing for genetic targeting therapies is really important in metastatic castration-resistant prostate cancer. It is a critical message that we need to do germline and somatic testing for these treatment options when we get to the mCRPC space if we have not already performed those assessments.

 

This real-world study actually led by Dr Shore and presented at GU ASCO just 2024, so about a year ago, showed that just under 60% of patients in an mCRPC real-world cohort ended up having testing for HRR mutations. Among those who were positive, only about two-thirds actually ended up getting treatment with a PARP inhibitor in this real-world cohort. That really means that about 40% of patients never got the testing and about a third of patients who were eligible for treatment did not get the treatment that may have been really impactful for them.

 

[00:47:39]

 

Real-world Study of Treatment Patterns in mCRPC: Overuse of ARPI

 

Using real-world data, we can look at ourselves and say, as a community, we need to do better both in testing and in terms of targeting our treatments to those patients who are eligible. Further, I think there is real-world data that can show us that although we are increasing in our frequency of AR pathway inhibitor use, especially in earlier settings like metastatic hormone-sensitive prostate cancer, we are continuing to use AR pathway inhibitors in multiple lines of therapy, including first- and second-line mCRPC in settings where patients have already been exposed to those agents.

 

We know that the second AR pathway inhibitor will have limited activity and probably will not meaningfully benefit for a long period of time, a majority of patients. Having other therapies, particularly other therapeutic options with different mechanisms of action is really, really critical.

 

[00:48:28]

 

NCCN Guidelines: Recommended Treatment of mCRPC

 

The NCCN guidelines take into account where the patient has been in terms of prior treatment in each of these boxes to help us think really rationally and thoughtfully about prior exposure and possible resistance that may have come from the prior exposure so that we can plan next steps that are going to be hopefully avoiding those mechanisms of resistance.

 

[00:48:48]

 

Ultimately, to know where to go, we really have to understand we have been and consider that alternate mechanism of action.

 

[00:48:56]

 

mCRPC: Critical Factors for Treatment Decisions

 

Other things to consider, at least from my perspective, are the sites of metastases, visceral only, bone only, something else. How is the cancer progressing? Extremely rapidly? Is it symptomatic? Is it asymptomatic? Is the patient going to be a candidate for intensive therapies or chemotherapies, or really is that something that is not going to be possible for this particular individual? Can the patient isolate if getting a radioligand therapy, that is a beta-emitting agent that may cause some radiation or exposure to people in the family who are close by? Are there special aspects of this cancer that might be targetable? Things like DNA repair defect mutations or PSMA, or even MSI-high status with pembrolizumab. Ultimately, we always want to be aware of possible clinical trials and be really practical in terms of understanding that we can only offer therapies that we have at our given location. Ensuring that we have access to as many therapies as possible is important.

 

EZH2 Inhibition

 

[00:49:55]

 

Mevrometostat: Epigenetic Therapy via EZH2 Inhibition

 

Let us dive into EZH2 inhibition. Mevrometostat is a drug that does target EZH2 as we talked about earlier. EZH2 is a protein that is over expressed in castration-resistant prostate cancer and is also associated with a poor prognosis. Mevrometostat is a selective inhibitor of this enzyme and early studies of mevrometostat-enzalutamide showed that this was both a manageable combination in terms of toxicity but also seemed to have a possible promising clinical activity.

 

[00:50:28]

 

Multipart, Phase I Trial of Mevrometostat

 

The phase I trial of mevrometostat really had several parts with the second part being a randomized dose expansion, particularly looking at patients with mCRPC because in many of these studies there are other tumor types included in early phases. In this dose expansion that included patients with mCRPC and no prior abiraterone in less than or equal to 1 prior chemo, patients were randomized 1-to-1 to receive enzalutamide, which should have been highly active in this setting or enzalutamide plus mevrometostat. The primary endpoint here was rPFS by the investigator.

 

[00:51:08]

 

Enzalutamide ± Mevrometostat in mCRPC: rPFS by Investigator

 

What we can see is that there was a prolonged rPFS radiographic progression-free survival with the combination including mevrometostat over the active control arm here of enzalutamide alone with a 49% reduction in the risk of progression or death and about an 8-month improvement in median rPFS. This is certainly an early-phase study that gives us a nice signal and something to build on, and I think has led to excitement about this combination.

 

[00:51:38]

 

Enzalutamide ± Mevrometostat in mCRPC: ORR

 

Here we can see the mevrometostat and enzalutamide combination in the way that it decreased measurable disease on the left for the combination, and on the right for enzalutamide alone, suggesting a benefit to the combination of mevrometostat with enzalutamide over enzalutamide alone.

 

[00:51:55]

 

Enzalutamide ± Mevrometostat in mCRPC: PSA 50 Response

 

Here we can see that PSA50 response showing a better PSA50 response in that waterfall on the left with the combination vs on the right with the enzalutamide alone.

 

[00:52:06]

 

Enzalutamide ± Mevrometostat in mCRPC: Safety

 

The safety data does suggest that there is some additive safety issue or adverse events I should say, associated with the combination as we would expect. The majority of these are actually grade 1 or grade 2 with very few of them being greater than or equal to grade 3. Again early study, relatively small, 81 patients. We will have to see where this goes in terms of further follow-up, but they seem to be GI related for the most part as well as for fatigue and anemia.

 

[00:52:35]

 

Key Ongoing Phase III Trials of Mevrometostat in mCRPC

 

Multiple ongoing studies of mevrometostat and mCRPC, and these patients all have mCRPC, no prior chemotherapy for mCRPC. You can see the randomization here to mevrometostat with enzalutamide vs docetaxel and enzalutamide. In the study on the right-hand side, you can see it is mevrometostat enzalutamide vs placebo and enzalutamide and rPFS is the primary endpoint in both of these settings. Large trials here that are phase III hopefully will be positive for us, and we can have new options at some point in the future.

 

CYP11 Inhibition

 

[00:53:08]

 

Opevesostat: Mechanism of Action

 

CYP11 inhibition is another strategy and opevesostat is the drug that is really doing this maximally upstream inhibition of the steroid synthesis pathway. We are all quite familiar with this pathway from abiraterone, which can inhibit or does inhibit CYP17A1 as you can see on this diagram in the middle of the screen where those little Xs are. However, opevesostat is up higher in the chain at CYP11A1, which, of course, when we inhibit that is going to cause a much greater downstream effect and the lack of production of many, many, many more steroid hormones.

 

[00:53:49]

 

CYPIDES Phase II Trial of Opevesostat in mCRPC: Baseline and Patients Characteristics

 

The CYPIDES trial was the phase II study of this drug in mCRPC and this included an early-phase trial with patients who had had at least 1 prior line of therapy. If we look on the right-hand side, we can see that most of these patients had had docetaxel, many had had both abiraterone and enzalutamide, and most had had an AR pathway inhibitor here. Many had had both chemo, so very heavily pretreated.

 

[00:54:16]

 

CYPIDES Phase II Trial of Opevesostat in mCRPC: Unconfirmed Best PSA Change

 

Here we can see the best PSA change for patients treated in this early-phase study. The waterfall plots suggest that on the left-hand side there is a pretty extreme decrease in that PSA in terms of number of patients. These are patients who had androgen receptor ligand-binding domain-activating mutations. Really, a population that might be considered to have perhaps more aggressive disease because of this resistance pathway that would have evolved in the setting of exposure to an androgen receptor-targeting type agent. On the right-hand side, we can see the responses among patients with androgen receptor allow you can binding domains that were wild-type. Still some responses here, though, perhaps not as pronounced.

 

[00:55:01]

 

CYPIDES Phase II Trial of Opevesostat in mCRPC: Duration of Treatment and Best ORR

 

Here we can see the duration of treatment really suggesting for some patients there was relatively durable response. On the right-hand side, this is resist measurable disease suggesting the benefit. Perhaps a little more so in those patients with ligand binding domain activating mutations, but also some responses in the wild-type.

 

[00:55:22]

 

CYPIDES Phase II Trial of Opevesostat in mCRPC: AEs

 

Here we can see the adverse events suggesting that many of the side effects associated with this very high steroid synthesis inhibitor are related to adrenal effects, things like adrenal insufficiency or hyponatremia. We can also see some low level of cytopenias, but most of these patients had grade 1 or 2 events as their worst event. Importantly, I should say that this drug is given with both dexamethasone and fludrocortisone, so both are glucocorticoid and mineralocorticoid steroid replacement.

 

[00:55:54]

 

OMAHA-01A: Ongoing Trial of Opevesostat Alone or in Combination in mCRPC

 

Here we have the OMAHA-01A ongoing trial of multiple combinations with this particular agent including combination with olaparib, docetaxel, cabazitaxel, and then a group with opevesostat alone.

 

[00:56:08]

 

Key Ongoing Phase III Trials of Opevesostat in mCRPC

 

Key ongoing trials looking at the mCRPC population, both pre-chemotherapy as well as post-chemotherapy, using this drug again with dexamethasone and fludrocortisone and comparing it to either or enzalutamide in these settings with radiographic progression-free survival and overall survival endpoints.

 

PI3K-AKT-mTOR Pathway Inhibition

 

[00:56:28]

 

Moving along to the PI3K and AKT-mTOR pathway.

 

[00:56:33]

 

Capivasertib: Mechanism of Action

 

Capivasertib is a drug that really targets this pathway, and we know that this pathway is often going to be overactive in cancer cells does help lead to increased cell survival and ability for them to replicate. A PTEN deficiency can really lead to hyperactivity of this particular pathway. When capivasertib is used, particularly perhaps in a PTEN-deficient tumor, this might be a highly active way to inhibit one of the mechanisms of this cancer cell survival and proliferation.

 

[00:57:03]

 

ProCAID Trial of Docetaxel ± Capivasertib in mCRPC: OS Results in ITT Population

 

This was studied in the ProCAID trial of docetaxel plus or minus capivasertib and mCRPC. Here you can see that there was a slight separation of curves with the capivasertib having a better survival in this ITT population vs placebo with a median follow-up here of just over 30-some months when the hazard ratio of 0.7.

 

[00:57:25]

 

ProCAID Trial of Docetaxel ± Capivasertib in mCRPC: OS Results With or Without Prior ARPI Exposure

 

Here we can see that that actually seemed to be most pronounced among patients who had had prior AR-targeting agent treatment, and those patients without prior AR treatment maybe did not have as pronounced of a response.

 

[00:57:40]

 

CAPItello-280: Capivasertib + Docetaxel vs Docetaxel in mCRPC

 

Here we can see the CAPItello-280, capivasertib, and docetaxel vs docetaxel study looking at patients with mCRPC.

 

[00:57:50]

 

Importantly, this study was actually just discontinued about a month and a half ago because the data monitoring committee really found that there was a low likelihood that they were going to meet the primary endpoints here of OS and rPFS, so this was stopped.

 

[00:58:06]

 

CAPItello-281: Abiraterone ± Capivasertib in PTEN-Deficient mHSPC

 

However, the CAPItello-281 study, which is looking in the metastatic hormone-sensitive prostate cancer population in PTEN-deficient tumors, was actually reported to be a positive trial. This was patients with PTEN loss and metastatic hormone-sensitive disease randomized to capivasertib and abiraterone vs abiraterone alone. A press release, as I said, did show or state that they met the primary endpoint of radiographic progression-free survival. We will wait for the presentation of this data.

 

[00:58:37]

 

SNARE: Neoadjuvant Intensified ADT + Capivasertib for High-Risk PTEN-Deficient Prostate Cancer

 

SNARE is looking at this combination of ADT and capivasertib in patients with PTEN-deficient tumors, even in a neoadjuvant setting. We will see how that goes.

 

PROTAC Protein Degraders Targeting AR

 

[00:58:47]

 

BMS-986365: PROTAC Protein Degrader Targeting AR

 

To finish off with the PROTAC, these are proton-degrading and targeting the androgen receptor. This first agent is BMS-986365. This data here is from a multicenter phase I, where they are doing a dose finding with this particular drug. PSA responses were seen with BID dosing, and the maximally tolerated dose was actually not reached.

 

[00:59:11]

 

Phase I Trial of BMS-986365 in mCRPC: PSA Response by AR Status and Dose, and rPFS by AR-LBD Status

 

Here we can see the PSA response by the androgen receptor status, both wild-type and mutated ligand-binding domain. Again, an escape pathway or resistance for patients exposed to androgen receptor-targeting agents or ADT of any kind. PSA responses were actually observed in both of these settings.

 

[00:59:30]

 

Phase I Trial of BMS-986365 in mCRPC: rPFS by Prior chemotherapy

 

Here we can see this drug rPFS by prior chemotherapy exposure, suggesting those patients who had not had prior chemo may have an even longer median rPFS than those patients who had been previously exposed to chemotherapy who of course have more heavily pretreated disease in most cases.

 

[00:59:49]

 

ARV-766: PROTAC Protein Degrader Targeting AR

 

A second agent here, ARV-766. This is a PROTAC protein degrader-targeting androgen receptor. Just a separate agent here, really making sure that this one is targeting these several more common androgen receptor ligand-binding domain mutations.

 

[01:00:08]

 

Phase I/II Trial of ARV-766 in mCRPC

 

Here we can see the phase I/II trial showing that PSA response, which looks pretty pronounced both at the PSA30 and PSA50 cutoffs.

 

[01:00:17]

 

ARV-766 Monotherapy in mCRPC: Tumor Response and DoT in Patients With AR-LBD Mutations

 

Here we can see the duration of treatment in those swimmer's plots, with many patients still having ongoing therapy even after many weeks on treatment.

 

[01:00:28]

 

ARV-766 Monotherapy in mCRPC: Safety

 

The safety events here show that there were no dose-limiting toxicities for this agent either, and the maximally tolerated dose was not reached in this phase I.

 

Let's Revisit Our Survey

 

[01:00:37]

 

Let us finish up with our survey here.

 

Posttest 1: When speaking with a colleague, how would you describe the primary mechanism of action of mevrometostat?

 

Back to those questions. This is our posttest. When speaking with a colleague, how would you describe the primary mechanism of action of mervometostat?

 

We did pretty well with this on the first try, so hopefully we do not get worse. All right, guys. Please answer now.

 

All right. Let us see how we have done. Good job everybody. All right.

 

[01:01:20]

 

We did talk about this mervometostat is a direct inhibitor of EZH2, so fantastic.

 

[01:01:23]

 

Posttest 2: Which of the following patient populations with mCRPC is eligible for enrollment in the ongoing randomized phase III MEVPRO-1 and MEVPRO-2 trials?

 

Next question here. Which of the following patient populations with metastatic CRPC is eligible for enrollment in these phase III trials? Is it those previously treated with ADT and chemotherapy and various lines as you can see, or those with ADT and no prior chemo?

 

Please let us know now.

 

All right. Let us see how we have done. All right. Excellent. We have certainly improved. Great. This is for patients treated with ADT and no prior chemo for mCRPC. All right.

 

Thank you, guys. Dr Ryan will talk next.

 

Targeting Cell Surface Proteins and Immune-Directed Therapies

 

[01:02:14]

 

Dr Ryan: All right. Well, thank you, Alicia and always a pleasure to be sharing the stage with the 2 of you to talk about novel directions in prostate cancer. I am going to talk about something that actually is quite exciting. That is not to imply that the other stuff is not exciting. What I am saying is that there are a number of new directions that we are going and targeting the cell surface proteins, and this has grown so much in the past couple of years.

 

[01:02:39]

 

Disclosures

 

These are my disclosures.

 

[01:02:40]

 

Patient Case: a 66-Yr-Old Man With Prostate Cancer

 

Let us consider a patient case as we walk through this. A 66-year-old African-American man with a history of localized prostate cancer who had underwent a radical prostatectomy. He had a Gleason 4+4, Gleason grade 4 prostate adenocarcinoma. He had extra capsular extension and a positive right apical margin.

 

After surgery, he developed a rising PSA about a year later. PSA rose from 0.03 to 0.12 to 0.6 to 1.7 over 12 months consistent with a doubling time of 3 months.

 

[01:03:20]

 

He undergoes a bone scan and a CT scan of the chest, abdomen, and pelvis that was negative for evidence of recurrent disease and his testosterone, which I encourage all to check testosterone on patients even before we have done hormone therapy just to make sure they are in the normal range. His was in the normal range. This patient had a rising PSA serologic relapse, biochemical relapse, we will call it. He started on treatment with a drug with enzalutamide for nonmetastatic. This should be hormone-sensitive prostate cancer in the setting of the rapid PSA doubling time.

 

[01:03:54]

 

Again, his PSA started to rise over a year later and next 3 months. Now he has a CT scan and a PSMA PET scan, which reveals several retroperitoneal lymph node metastases, but no other sites of disease. At this time, he has been diagnosed with metastatic castration-resistant prostate cancer.

 

[01:04:14]

 

Pretest 3: Which of the following would you recommend as the best next step for this patient?

 

Pretest question. Which of the following would you recommend as the best next step for this patient with metastatic castration-resistant prostate cancer?

 

1. Cryotherapy to the pelvic lymph nodes for recurrent disease;
2. Add olaparib plus abiraterone first treatment;
3. Explore options for clinical trial enrollment and standard treatment through reputable sources of information for patients;
4. Pursue surgery to remove the retroperitoneal nodes that appear involved on the PSMA PET scan.

 

While you are thinking about those questions, I will just show you 1 more time that scan that we had. As you can see, retroperitoneal lymph nodes, but no other sites of disease. You can see them right below the kidney. That is the extent of the disease in this case, a man with mCRPC. Go ahead and answer your question.

 

Here is what we do; 45% of you are good doing abiraterone plus olaparib, 36% are exploring options for clinical trial enrollment and standard treatment through reputable sources of information for patients, and 18% of you are pursuing surgery to remove the retroperitoneal lymph nodes that appear involved on the PSMA PET scan.

 

Combining Immune Checkpoint Inhibitor With a Tyrosine Kinase Inhibitor

 

[01:05:45]

 

We will come back to that question maybe when we have our panel discussion. Interesting question, interesting answers. I am going to focus on the cell surface. We are going to talk a little bit about immune checkpoint inhibition with tyrosine kinase because there is a little bit of activity in that area, a dynamic approach.

 

[01:06:01]

 

Rationale for the Use of Cabozantinib + Atezolizumab

 

This has been an interesting journey for this combination of atezolizumab, a drug you probably know well as a PD-L1 inhibitor and cabozantinib, which has been around a long time, is actually an FDA-approved drug for kidney cancer, but has for many, many years shown some activity in prostate cancer.

 

There has been a lot of work around how does cabozantinib actually work in prostate cancer. It does inhibit VEGFR and that is probably where a lot of its activity comes from in kidney cancer. It has activity against MET, which also may underscore its activity in kidney cancer. However, there is a growing body of awareness on our ability to target the extracellular matrix. That may be one of the areas where cabozantinib demonstrates some benefit. Tumor-associated macrophages are known to be affected, and this drug may, in fact, enable the activity of macrophages in the extracellular environment, thus allowing immunotherapy to be slightly more effective. It was hypothesized, and it has been demonstrated preclinically that this combination seems to be a rational one.

 

[01:07:16]

 

COSMIC-021 Trial of Cabozantinib + Atezo in mCRPC: ORR and PSA Response

 

This was looked at in an early study called COSMIC-021, which was cabozantinib plus atezolizumab in mCRPC. As you can see with these waterfall plots, they were in a fairly heavily pretreated patient population, a number of patients who had disease change in terms of some shrinkage of target lesions on the left, as well as decline in PSA from baseline shown here on the right, including patients with visceral disease and extra prosthetic lymph nodes.

 

[01:07:50]

 

CONTACT-02: Cabozantinib + Atezolizumab Vs Second Novel Hormone Therapy in mCRPC

 

That led to the design of the CONTACT-02 study, again looking at cabozantinib plus atezo as this combination and comparing it to a second next-generation hormonal therapy, either enzalutamide or abiraterone. This was a study that was first demonstrated about 3 years ago now and showed the following data and this was presented by Niraj Agarwal about 2 years ago at ASCO GU.

 

[01:08:20]

 

CONTACT-02: PFS

 

Quite a bit of controversial data but demonstrated some activity of this combination. Again, you have got 2 wholly different drug classes here where you have got the PFS improved slightly, about a 35% reduction in the risk of disease progression associated with a P value of 0.007 with fairly favorable safety profile suggesting that this may be a novel direction that we can take in this disease.

 

[01:08:47]

 

CONTACT-02: PFS in Select Subgroups

 

More to the point though, and perhaps more provocative is when we looked at areas of involvement such as the liver and bone metastases, we actually see that in the setting of liver disease, it looks like this immunotherapy and targeted therapy approach, again targeting the extracellular matrix maybe have more implications in those patients who have liver metastases. The numbers are small here, but it is a pretty significant improvement, especially in this group of patients with liver metastases who are known to have a very poor prognosis overall.

 

In those who have bone metastases, in addition, we see a modest improvement in progression-free survival, again suggesting that this group may benefit as well. There are 3 compartments we can think of the disease, liver, bone, and lymph node. As we would all agree, I think liver and bone are probably the two with the greatest implications on poor prognosis. It is very heartening to see this data come and quite provocative.

 

[01:09:46]

 

CONTACT-02: OS in ITT

 

COSMIC-O2, the overall survival, however in this study, was not statistically significant and that has been one of the challenges in its interpretation and implementation over time.

 

[01:09:58]

 

Evolving Era of Targeting the Cell Surface: Targets Under Investigation

 

We will wait to hear more about this data, that data is under review, but this trial continues to mature and be evaluated by regulatory authorities for consideration. That got us thinking a little bit about the extracellular matrix about things outside of signaling pathways. Dr Morgans talked about these signaling pathways in the cell, the androgen receptor, EZH2, etc, all very, very important. However, we have an opportunity to target the outside of the cell, which may also have implications. PSMA, B7-H3, STEAP1, DLL3, TROP2, and CD46. These are all proteins that pretty much exist on the surface of most adenocarcinomas of the prostate, and as we will see, some of them as they differentiate or become more aggressive, they decrease expression of some of these targets and increase expression of some of these others. This type of thinking, this class of therapies if you will, is really going at the heart of some of the changes that evolve in tumor types under the course of treatment resistance.

 

[01:11:02]

 

There are a few others that are still not yet fully explored. ROR1, FAP, CXCR4, PSCA, which has been around a long time, HER3, and CD36, multiple, multiple ongoing trials. I will try to list them for you a little bit.

 

[01:11:17]

 

Preliminary Findings: PSMA Targeting

 

PSMA is probably the most credentialed target on the extracellular surface that we have in prostate cancer. It has a number of advantages, of course, because it is expressed almost ubiquitously on prostate cancer cells, in particular the adenocarcinoma component. Patients who have neuroendocrine component are less likely to express PSMA, but the other thing that cell surface proteins bring to the clinic for us or the opportunity to target them through multiple modalities, radioligand therapies, antibody–drug conjugates, CAR T-cells, bispecific T-cell engagers, and you can see this is a current list of those where there are trials being studied with these different modalities of essentially tumor-targeting with PSMA. The payloads differ, the mechanisms differ, but this is the target.

 

[01:12:15]

 

Preliminary Findings: STEAP1, TROP2, B7-H3 Targeting

 

STEAP1, TROP2, B7-H3, again ADCs, bispecific T-cell engagers for all of these are in the clinic. We are seeing encouraging results including in some cases response rates in CRPC patient populations of 40% as is the case with the B7-H3 antibody, drug conjugate, sacituzumab govitecan available and other cancers targeting TROP2, modest response proportion of only 9%. You see that there are some differences in these, probably related to drug resistance factors, probably related to variable expression of these targets on the cell surface.

 

[01:12:56]

 

Preliminary Findings: CD46, DLL3, and TF Targeting

 

CD46, DLL3, and TF-targeting are also being looked at in a number of different contexts. An antibody–drug conjugate targeting CD46 from a drug called FOR46 demonstrated PSA50 declines of 45.2% of patients. A lot of encouraging findings here as we think through this.

 

[01:13:23]

 

Characteristics of Cell Surface Targets

 

Let us talk about this class of targets if you will, and why they are advantageous high in tumor vs high in healthy cells, that would, of course, be the ideal tumor target. Because the challenges, the side effects of these therapies, most notably seen with PSMA targeting for example, is the off-tumor on-target effect. Dry mouth that comes with PSMA-targeted radioligand therapy comes because the salivary glands are packed with PSMA. It is not really a side effect of the drug, it is an effect of the drug. It is just that the target is there.

 

What we really want to find are tumors that have homogeneous expression of tumors and that would be quite advantageous. The other possibility is that even if in the setting where there is not homogeneous expression, where some of the tumor cells do not express the target, and you are delivering radioligand therapy or delivering even an antibody–drug conjugate, you may have a bystander effect where the tumor cells that are nearby that do not have the target may also be hit by the payload.

 

The other piece is how effective are, and we are learning a lot about this, how effective are this accessibility on the cell membrane, whether it is a radioligand therapy where essentially you are just putting radiation right next to the cell, whether you are giving an antibody–drug conjugate where you are trying to cause intracellular release of the drug and that requires that the drug, the antibody be taken up in an endosome and thus do its effect through lysosomal degradation or other factors. How much of the drug comes off the antibody before it goes off into the extracellular matrix? That is a key part of it. If you want to make a better antibody–drug conjugate, you want to have a good affinity for the cell surface, but you also want to have a drug that stays on the antibody until it gets to the surface of the cell and does not leak off into other areas because then a) you are going to have side effects and b) you are going to have less activity.

 

The other thing is, as I said in my opening comments, the underlying biology of the disease intracellularly drives a lot of things. If you have a cancer cell that is intrinsically resistant to radiation therapy because of some mutations in it, and you deliver a radioligand therapy, that radioligand therapy is going to be less effective. It does not mean that it is going to be completely ineffective. That is one of the opportunities, is we can help to overcome some of that resistance by giving more potent radioligands and a more potently binding antibodies, etc.

 

[01:16:05]

 

Investigational Radiochemicals and Targeting the Surfaceome

 

There are, as I like to say, a dizzying array of radiopharmaceuticals. This slide, I apologize, is impossible to read, but those of you watching at home can put your faces up to the screen, and you can see that there are a number of approaches looking at different isotopes, lutetium, actinium, lead, iodine, copper, astatine, etc. These can come in the form of a peptide ligand, you can have antibodies targeting these receptor surfaces. Then as you look at this circle, as you get closer and closer to the middle of the circle, you get closer and closer to drug approval.

 

In this setting of targeting the cell surface really have in the world of oncology with lutetium Lu 177 dotatate and lutetium Lu 177 vipivotide tetraxetan whenever it comes to radio isotope therapies. However, we are at the beginning, perhaps the end of the beginning of an onslaught of a number of these different targeting approaches. In prostate cancer alone, there are almost innumerable clinical trials underway and multiple companies getting into this space.

 

Next-Generation Immune-Directed Therapies: Bispecific T-Cell Engagers CAR T-Cell Therapies

 

[01:17:10]

 

Let me talk about next-generation immune targeted therapies, bispecific T-cell engagers, CAR T-cell therapies.

 

[01:17:18]

 

Rationale for Targeting Human Kallikrein 2 (KLK2)

 

We are seeing some encouraging activity of these in other cancers. A couple of targets you may not be aware of, KLK2 or human Kallikrein 2 is an antigen produced by prostate cancer epithelial cells. It is part of normal prostate physiology, by the way. PSA is KLK3. It comes in the same family and actually sits adjacent to the PSA gene on chromosome 19. As you might expect, it is enriched in prostate tissue and prostate cancer relative to normal tissues because this is not a protein that is really needed anywhere else. That makes it different from PSMA. We do not know why, but PSMA is on the salivary glands. KLK2 is not, and thus KLK2 is under investigation as a novel therapeutic target for multiple different modes of therapeutic delivery, whether it be radiologic therapy, CAR Ts, T-cell engagers, etc.

 

[01:18:08]

 

Mechanism of Action of CD3+ Bispecific T-Cell Redirection in Cancer

 

When we think about these approaches, let us think about the mechanism of action of a CD3 bispecific T-cell engager. You will frequently hear us refer to them as KLK2 by CD3. You might hear of PSMA by CD3, something like that. CD3 implies you have got something to bind to the T‑cell. That CD3 is a T-cell protein and KLK2 again as the targeting moiety. In this case, instead of delivering a radio isotope, we are using KLK2 to deliver the T-cells directly adjacent to the tumor type. There are a number of these. JNJ-78278343, is a humanized immunoglobulin GI bispecific antibody that is being tested in multiple clinical trials.

 

[01:19:02]

 

Phase I Trial of JNJ-78278343 in Advanced Prostate Cancer

 

Last year, there has been some early enthusiasm about this approach. This is the trial design of an international dose escalation dose expansion phase I study, which is looking at a number of different spaces in prostate cancer and working to assess the minimum anticipated biological effect level, or the MABEL, or the starting dose of these. Then from there we will go into looking at different disease types, whether it be the lymph node–only patients, those with liver metastases, visceral metastases, etc.

 

[01:19:36]

 

Xaluritamig (AMG 509): Mechanism of Action

 

Xaluritamig or AMG 509. Similar story, here what you have is you have a STEAP-targeted T-cell engager. Here you have STEAP by CD3, not KLK2 by CD3. This STEAP1 is a transmembrane protein highly expressed in prostate cancer, including about three-quarters or more of those with metastatic disease. Unlike PSMA, to some degree STEAP1 expression is a marker of poor prognosis. We are not only hitting a very prevalent target, we are hitting a target that actually appears to be somehow associated with poor outcome.

 

[01:20:14]

 

Phase I Study of Xaluritamig in Advanced Prostate Cancer

 

This was first reported a couple of years ago by Kevin Kelly from Thomas Jefferson, ongoing results from an open-label multicenter first-in-human phase I study.

 

[01:20:26]

 

Xaluritamig in Advanced Prostate Cancer: Activity

 

These were the results that have been now presented in Cancer Discovery. As you can see, a fairly high proportion of patients who have PSA declines, who have a change in measurable disease from their preexisting parameters and some very dramatic responses.

 

[01:20:47]

 

Xaluritamig in Advanced Prostate Cancer: Clinical Activity in Patients With mCRPC

 

Now, this is a therapy that requires inpatient hospitalization for administration, is associated with some cytokine release syndrome. However, even so after that, we do see patients with quite significant improvements in outcome as is demonstrated by these case examples that Dr Kelly presented.

 

[01:21:07]

 

Novel Anti-STEAP CAR T-Cell Therapies

 

STEAP is a new target. PSMA, KLK2, and now STEAP. You can see the number of these targets emerging and there are a number of mechanisms of action of anti-STEAP that can be done including CAR Ts. It is still early days for us to use CAR T-based therapy in solid tumors generally and in prostate cancer specifically. However, there are a number of ways of doing that, and there is the agent from AstraZeneca, AZD-0754, which is being tested in metastatic prostate cancer.

 

[01:21:40]

 

AZD0754: Anti-STEAP2 CAR T-Cell Therapy

 

This is a very interesting CAR approach insofar as what we are learning from CARs and solid tumors is that there is a resistance mechanism which is TGF-beta in the tumor microenvironment. That TGF-beta in the tumor microenvironment binds to a receptor on the T-cell, the TGF-beta receptor. If you can down-regulate the TGF-beta receptor on the T-cell, what you will have is a T‑cell that is immune, if you will, pardon the pun, or is resistant to the immunosuppressive effects of TGF-beta. There are a number of different approaches that are emerging like this, and this is one that is in the clinic now.

 

[01:22:21]

 

Tarlatamab: A Bispecific T-Cell Engager Targeting DLL3

 

Last couple, tarlatamab is a DLL 3 T-cell engager. DLL3 is highly expressed in neuroendocrine cancers, in particular small-cell lung cancer and neuroendocrine prostate cancer. This drug is actually approved for use in small-cell lung cancer, and it is demonstrating effects in prostate cancer as well.

 

[01:20:42]

 

DeLLpro-300: Tarlatamab Monotherapy in Metastatic Neuroendocrine Prostate Cancer

 

Rahul Aggarwal, my former colleague from the University of California, San Francisco is leading a lot of these efforts in identifying the neuroendocrine patients and then targeting them with this approach.

 

[01:22:52]

 

DeLLpro-300: Baseline and Histologic Characteristics

 

The trial that is ongoing or that is been presented is called DeLLpro-300. This actually included patients with small-cell lung cancer as well as prostate cancer with neuroendocrine features and did demonstrate again a small proportion of patients who had fairly significant responses.

 

[01:23:07]

 

DeLLpro-300: Response and DoT

 

Even though the number of patients responding to this approach is relatively small, this is a very aggressive variant of prostate cancer. This is a very interesting highlight that is something that we need to tease out in terms of figuring out how we can enrich our patients and identify those patients who might benefit from this particular approach. We are still waiting on sort of more definitive data, but we do see patients who are benefiting, not the majority, but a proportion of them who do benefit and have remissions that continue to go on.

 

[01:23:41]

 

Patient With DLL3-Overexpressing NEPC Who Achieved a PR

 

He demonstrated a case here, delta-like ligand 3, overexpressing neuroendocrine prostate cancer treated with this approach. You see regressions of the disease in the liver, and you see what is also required, which is histological confirmation of neuroendocrine prostate cancer.

 

[01:24:00]

 

DeLLpro-300: Safety

 

Like a lot of these therapies, there are cytokine release syndrome, quite common grade 2 in about 1 in 5 patients who receive it. However, 75% of patients experience some degree of immune side effects and cytokine release type syndromes.

 

[01:24:19]

 

Precision Chemotherapy With Antibody-Drug Conjugates

 

We are entering into an era when we have a lot of these targets where we will be able to move forward with targeting things like CD46, PSMA, B7-H3, etc. I think we have a lot to learn and hopefully in future years we will be able to go through this and think about this.

 

[01:24:35]

 

Tumor-Specific CD46 Conformational Epitope

 

The last one that I am covering is CD46, which was identified by the team I used to work with at UCSF many, many years ago. I remember hearing first lectures on the expression of this protein and how it could be a drug target, and here we are 15-plus years later where we have demonstrated that it is overexpressed in prostate cancer, and we have demonstrated that FOR46, a CD46 immune modulating antibody–drug conjugate is demonstrating clinical activity. Again, this has work by Dr Rahul Aggarwal out of UCSF, so he is really taking the lead in that. There are additional agents that are looking additional approaches that are moving forward with this.

 

[01:25:17]

 

APEX-01 Trial of ARX517 in mCRPC

 

The final one, I think is my final one, which is John Shen's work that was presented at ESMO, which is another antibody, anti-PSMA antibody–drug conjugate. You are well familiar with radioligand therapies, but we see here ADCs against PSMA may have a role in this as well.

 

[01:25:36]

 

B7-H3 as a Target in mCRPC

 

And B7-H3 additional target, which is something of a checkpoint inhibitor family member, the B7 family of checkpoint inhibitors very highly expressed in prostate cancer and may thus enable us to target the immune system a little bit more directly.

 

[01:25:54]

 

Conclusions

 

Basically, to conclude, I think you have gotten a potpourri of all of the cell surface targets that are available and all of the ways that we can target the cell. Now that we know the targets, we can think about what is the payload: radioligand therapy, antibody–drug conjugate, CAR T-cell. There are a lot of these parts to watch for as we think about this.

 

Key is to get these trials enrolled, give these exciting new agents their test, and see if they work, and see if the safety profile fits with what we will find acceptable for our patients.

 

With that, I will conclude and thank you for your time. I think we are going to have our roundtable, and I am going to stay up here and talk a little bit about this topic.

 

Roundtable: Addressing Inequities in Prostate Cancer

 

[01:26:38]

 

Discussion

 

I just listed, Alicia, I do not know how many drugs, I forget the number, but it is a lot, very exciting. This is amazing science coming out of top labs and it is really great. However, we have this problem, which is even when we develop new therapies, we still see disproportionately poor outcomes for certain populations, and in particular in the US, Black men and certain other minorities have poor outcomes. I just wonder, in your daily practice, you come to us as a leader from 2 types. One is you have a daily practice, you take care of prostate cancer patients, but you are also seeing the full landscape of what is available out there. What is your sense of where we are with our understanding of disparities and not only disparities in delivery, but biology of the disease?

 

Dr Morgans: I think we are really doing our best to understand both those social determinants of health and cultural factors related to long-term wounds that have been applied to certain populations from trials that were not necessarily ethical many, many years ago, and then longstanding disparities that exist in our country and in our medical practice, as well as trying to understand if there are any biologic differences that may contribute to some of the differences in diagnosis and in outcomes.

 

I think we do not yet have a complete picture here, but we do know that there are certain levers that we can pull that can make a difference. I think one of those is really being aware of the disparity, and we do try to talk about it, which is very important in forums like this and in our own practices with our teams, and making purposeful efforts to be really equitable in terms of those patients that we reach out to with clinical trials.

 

Sometimes those conversations may take longer if people have a personal background that may make it more challenging for them to consider engaging in clinical trials, whether they are Black, or whether they are White or whether who knows if they had a family experience or any person may have those challenges. However, I think especially when it comes to advancing the field, ensuring equitable offering and education around clinical trial opportunities is a really, really great way to start and might be a way for us to also ensure that the trial outcome data that we ultimately have is going to be something that applies to all of the people that we see in clinic.

 

That is one step that I try to make sure I am aware of. For any patient who meets criteria for different trials, I try to make sure that this is being offered, considered, and discussed even if the discussion takes longer or maybe is brief, you never know the person that you are going to talk to. This is one piece that I think we are trying to take and certainly appreciating everyone in the room who hopefully will also be considering these things when they are in practice.

 

Dr Ryan: Neal, you have for decades now been really at the forefront in completing clinical trials. Number of registrational trials have come through your practice and through your shop in South Carolina. You are obviously doing many things right. For those out there who are maybe less experienced than you on clinical trial enrollment and are concerned about this disparity issue, what are the important factors that you see in creating a clinical trial portfolio, number one, but also sitting down with individual patients and their families as you discuss clinical trial enrollment?

 

Dr Shore: Thanks. I appreciate the question. I would maybe take getting patients, particularly the underserved population, to appreciate the importance of a clinical trial. What I have learned on a personal level, and we have a fairly high African-American population, Latino population starting to increase where I am in the coast of South Carolina. We do not have a very large Asian population, but what I recognize is that language matters. Language matters a lot. How you potentially talk to someone who is college educated, graduate school educated, vs someone who is vocationally trained or somebody who came from rural South Carolina vs metro Boston, language really, really matters.

 

Then in our world right now where authenticity and trust is really under siege, particularly with social media, and I think probably I am in a safe space when I say because I am looking out and thinking everybody here are physicians and highly trained, we get so much noise on the Internet, crazy stuff that is out there, highly educated people and less educated coming in and asking for things that quite frankly, you know in your heart of hearts does not make any sense. How you answer those questions, they are well-intended, their families are well-intended, and try to steer them towards the importance of a clinical trial. I think there is a lot we could do better in terms of our own interaction, our body language, and the communication that we do and use with patients. Advocacy groups like ZERO, who are one of our sponsors tonight, they really focus on that a lot, and they have a lot of really good, helpful tips.

 

Second part of your question, what I have tried to do, early on, I thought about how do I select trials in prostate cancer per se, that just keep it to mCRPC that I want to have a trial option for the first-line and now second-line, maybe they are post-RP progressor, or maybe they are a post-PARP progressor doing genetic testing, or maybe now they are an RLT progressor or a chemotherapy progressor. I want to make sure that I have it covered. I actually take that same kind of construct throughout the entire spectrum of prostate cancer so that every patient who comes into the clinic, and I am a busy community clinic, is a trial patient until proven otherwise.

 

Dr Ryan: Great answer. I will just add all of us want to see progress against cancer. All of us want to see that more than 5 or 6% of patients enroll on clinical trials. It is really a team effort. It requires those of us who have the opportunity to help design the trials, it requires those of us, I include myself in this list of who may not be involved in the design of a trial, but have the opportunity to match a trial to a patient we are taking care of. It requires the patient and their families to understand something of the ambiguity and even the risk of enrolling in clinical trials.

 

The word that Neal said, I am just going to underscore it, is trust. Patients will put themselves in a situation of facing ambiguous outcomes. They will put themselves in a position of the potential for toxicity in an early-stage trial if they feel that their physician has their best interest at heart. That is the core ethical principle through which we do clinical trials, which is we have positive therapeutic intent. That is something that I think we really need to convey to patients that the reason we are doing a clinical trial is that we want them to do better. We want better outcomes for patients, and we want to have a greater variety of options available for patients.

 

With that, we will close this panel discussion, talk a little bit about ZERO. I have been involved with ZERO for many years, actually thanks to you, Alicia. You introduced me to them many years ago. You are actually on their board and have been involved in many levels. One of the things I would say is that ZERO's primary mission is patient engagement, patient education, patient resources, and helping patients understand and be empowered for the journey that they find themselves in while receiving treatment for prostate cancer.

 

There are a number of online sources at zerocancer.org that you can make available for your patients. This is an example of one that says, why is my tumor being tested for biomarkers, or was my tumor tested for biomarkers? I started out my comments tonight by saying, we know so much about prostate cancer because we do genomic testing. If we are not doing genomic testing, we are not going to know so much. We have to engage our patients to some degree in that dialogue as well.

 

There are really some beautiful graphics, some beautiful handouts that I think you can print for your patients or just refer them to the website. Jeremy from ZERO is here in the audience tonight and might be able to chat with you after if you find it of interest. However, I had a chance to go through these and these are really great fact sheets that talk about the issues about things. You can go to your doctor questions, you can go to your doctor. These are handouts and materials that you can make available for your patients, questions for your doctor, questions about clinical trials, etc. All really good resources and they have many resources as well, including not just informational but also people, a helpline, a mentor program, a clinical trial finder, and multiple in-person and educational events. I have participated in a number of those. I have actually gone to Capitol Hill on behalf of Zero Prostate Cancer to talk about their resources and advocating for prostate cancer research in the country. Alicia, any comments on ZERO or did I nail it?

 

Dr Morgans: I think you definitely nailed it, but I think there was a lot on the screen and I think you summed it up well, lots of beautiful graphics, but I just send my patients to the website. It is really easy, www.zero.org, and they can go there, and they can reengage with that site to find the resources that are most meaningful for them at the time that they need them. I really want to point out the ZERO360 program, which helps them with financial support and at least counseling around some of the financial struggles that they may have. There may not be options for everybody, but I think a lot of people have things that can be sorted out, and the team actually has the funding to support that.

 

Then the support groups and also the mentor program, which is a 1-on-1 support system that can be helpful because not everybody wants to be in a larger group and share their story with many people, but sometimes they still really need help. There are some really dedicated and generous individuals that have given their time to actually do that 1-on-1 support, which I think is wonderful.

 

Dr Ryan: You have got these QR codes here in the graphics which you can give to your patients and download and access them yourself.

 

Dr Morgans: Let me just add, I do not remember websites well, so www.zerocancer.org is really what the website is. Please do not to get that wrong.

 

Let's Revisit Our Patient Case

 

[01:37:52]

 

Dr Ryan: Thanks. Okay. Very good. Let us revisit our case after that great discussion.

 

[01:37:57]

 

Patient Case: A 66-Yr-Old Man With Prostate Cancer

 

We remember we had this gentleman who had the rising PSA, he went on enzalutamide and ADT, and then he ultimately progressed to having metastatic prostate cancer. We had a number of options and somewhat common scenario, which is a relatively low volume of disease on the one hand, but on the other hand it is already resistant to hormonal therapy.

 

[01:38:21]

 

Posttest 3: Which of the following would you recommend as the best next step for this patient?

 

What did we want to do for this patient? I believe what we are going to do is we are going to ask the question again.

 

1. Should we do focal therapy to the lymph nodes;
2. Should we give them olaparib and abiraterone;
3. Should we explore options for clinical trial enrollment and standard treatment through reputable sources of information for patients? I do not know, like zero cancer.org might be one.
4. Should we pursue surgery to remove retroperitoneal nodes that appear involved in the PSMA PET scan.

 

Okay. 90% of you are going to consider exploring options for clinical trials, and not only clinical trials, but helping educate your patients through the online and other available resources that are reputable and vetted by professionals. We all know that there is a lot of misinformation in the world and I think the key underscore of that question is reputable resources. The 3 of us up here have worked with ZERO for years and find it to be a very good resource, and I refer our patients over to it.

 

[01:33:40]

 

With that, this is the answer. The patient can pursue information for possible clinical trials through prostate ZERO website, for example, which is a reputable site for patients to find information. We did not go into this. Neal, if you want to comment, feel free. Cryotherapy and surgery are not typically done for lymph nodes in CRPC mostly because at least I do. I think of this as a systemic disease. Olaparib and abiraterone would not be recommended as this patient does not as far as we know, have a BRCA1 or BRCA2 mutation.

 

All right. We are going to head back to Neal to talk about lutetium-177, PSMA-617 and beyond. Neal.

 

Targeted Radiation: ¹⁷⁷Lu-PSMA-617 and Beyond

 

[01:40:25]

 

Dr Shore: Well, it is really clear to me. Chuck and Alicia did really a lot of the heavy lifting on talking about where we are today in the complexity and the excitement in the clinical trial landscape, the novel MOAs, the different markers that are out there, cell expressing markers, it is an incredible time.

 

Prostate cancer, like many other cancer types, we have become very successful. However, it takes a multidisciplinary team and you take subspecialization now. It is really hard to be a generalist, to be a community oncology generalist. I think it is virtually impossible similarly to be a generalist and radiation oncology, or nuclear medicine radiology, or urology. It really does take a multidisciplinary team to do this well.

 

Then likewise, I think we have realized that when it comes to patients, it is a team event. It is their partner, it is their family, it is trusted friends, it is other support mechanisms because it is overwhelming. That is where I think Chuck makes a great point in these trusted resources. ZERO is fantastic. There are a lot of these sources out there now and that Is what we have to do because it is so complex in a good way, we have a lot of different things to offer patients. Let me now just go through some recent data that is out there now. Level 1 evidence, so to speak, guideline recommended therapies for the most part, now they are changed where we are.

 

[01:42:04]

 

Faculty Disclosures

 

My disclosures.

 

[01:42:04]

 

Discussion

 

Quick roundtable. I may just only do one of these for you to answer because of time purposes. We see earlier use of lutetium-PSMA-617 produce better outcomes vs later use combinations. What are your perspectives on radio ligands? What is the role of alpha emitters? Let me just make it really open-ended. Let everybody in the audience think about these questions. They are really important, but I will make it a little bit simpler for Alicia and Chuck. The bread and butter starting in 2004, up until 2010 and mCRPC was docetaxel, docetaxel and pretty much nothing else. Then we see this just cascade of new therapies, targeted therapies, other parenteral therapies, radiopharmaceutical immunotherapies. Where do you think we are right now in the world of RLT, radioligand therapy? It is an overarching. Why is it important that our medical oncology colleagues, this is ASCO, recognize the importance of this arena, Chuck?

 

Dr Ryan: It is very important because there is a survival advantage associated with the use of lutetium 617 in the post-chemotherapy setting. There is a really nice radiographic progression-free survival advantage in the chemotherapy-naive population. It is here. It is here to stay, and it is now widely available in the country and will be soon in many other countries.

 

I think that one of the key things to know is that this is not chemotherapy in terms of how you think about it. Those of us who are trained in as oncologists who think of chemotherapy as every 3-week cycles, you give as much as you can, there is a slightly different dynamic to the use of radiologic therapies that we are still learning. Some patients have exquisitely sensitive forms of the disease to this treatment and thus may get 2 treatments and do very, very well and then get treated later, which is a different mentality than from the chemotherapy where those of you who trained in oncology learned about the Gompertzian model of cell kill and things like that. We are not quite sure that applies here. There is a lot that we need to learn about how to optimally dose these over time in patients.

 

Dr Shore: Great point. Alicia, your thoughts?

 

Dr Morgans: Yes, I think to your point earlier, and I think Chuck was alluding to this too, and did with his little circle slide, that we are really scratching the surface that this is one of the earlier isotopes in one of the earlier targets. However, I think we will see more and more isotopes integrated into our landscape and more and more targets because perhaps people can have various different RLTs over the course of their dealing with the disease. Patients seem to really like these agents for the reasons that you mentioned, that there can be some patients who have this very, very sensitive disease and then have maybe a treatment-free interval before possible retreatment. This could be coming at some point in the future. Especially when we see patients living for years and years, they want to have both really excellent cancer control, but they also want to keep living their lives. These drugs, for the most part, for many patients, help them continue to feel really quite well, even as they are using intensive therapies for their prostate cancer.

 

I think we will see more agents, more options, and continue to see over time an improvement in our ability to keep people safe and well, and possibly get multiple agents over time while they deal with the disease.

 

Dr Shore: Great points. I think across all oncology, we are all starting to recognize the importance of intensification and yet, at the same time for some patients, depending upon their responsiveness deintensification. We can now use a little bit of the art of medicine there and tailor it to patient's desires, and I think that is great.

 

[01:46:13]

 

Patient Case: A 65-Yr-Old Man With mCRPC

 

Let us do a quick patient case, 65-year-old man, mCRPC. He is 65 now. Two years ago, he was diagnosed with de novo mHSPC, grade group 4, PSA 85 labs, normal, good performance status, gets a PSMA PET, he has got 3 axial spine lesions, a pelvic bone lesion, retroperitoneal pelvic nodes with significant avidity, presumably high SUV, no visceral lesions. He started on ADT and an ARPI, goes from an 85 down to a 0.5, appropriately so he gets germline and somatic testing that is negative, that should be standard of care in every one of these patients. Then 2 years later, his PSA goes up, he is seeing the dreaded PSA rise, he is now 3.5. A repeat PET, he is positive in the retroperitoneal nodes. He has the same spine lesions, but there is a mention of 1 additional lesion.

 

[01:47:10]

 

Pretest 4: Which of the following would you recommend as the best next step for this patient?

 

Okay. Doublet therapy, he is now mCRPC, he has got some new lesions, it is all on PET. Which of the following would you recommend is the best next step for this patient?

 

1. Actinium-225;
2. Cabazitaxel;
3. Lutetium-PSMA-617;
4. Olaparib.

 

Okay. Well, drop the mic. All right. We are done. All right. Next slide. Wow, smart audience. Very good.

 

[01:47:57]

 

Factors Contributing to Treatment Decision-making

 

Okay. I mentioned it a minute ago, and I think we all recognize the days of being paternalistic. I walk in with a white coat, tell you what to do. That does not exist anymore. We have got to be better in our language and use language. We have to taper it and tailor it to who our audience is so they can trust us, and we are authentic, and then we ultimately get to the shared decision-making. Some people are more risk-averse, some people are more risk-tolerant or risk-seeking, and I call that preference value. That is very important. You can see all some of the concepts here that are very important that we as healthcare providers have to think about stage, tumor burden. What does the patient want? What are you comfortable with? You cannot necessarily offer everything. Unlike Chuck and Alicia, they have photographic minds. They remember everything. Then what treatment is going to be best for the patient?

 

[01:48:52]

 

ALSYMPCA: Efficacy of Radium-223 in mCRPC

 

Well, let us just talk. Let us go back a minute. Radium has been around for over 10 years now. This is the ALSYMPCA trial. This was really one of the first radiopharmaceuticals to basically show an impact. You can see here the OS benefit, and this is basically looking at patients who had no prior docetaxel vs post-docetaxel. Ultimately, the patients who are without docetaxel exposure actually did somewhat better in their hazard ratios and their median OS. However, this was demonstrating a well-tolerated therapy that really opened up a whole other MOA for us.

 

[01:49:34]

 

PEACE-3: Enzalutamide ± Radium-223 in mCRPC

 

However, it felt a bit off for a lot of folks when there was an earlier study that combined it with abiraterone called the ERA-223. I do not have time to go into all the details of that, but essentially, there were some interesting aspects of that study. Bone health agents or antiresorptives were not routinely used. A lot of these patients ended up having fragility fractures, and other fractures, and SREs. Then ultimately, at the end of the day, the combination of abiraterone and radium-223 led to some warnings, and it really put a bit of a damper on the combinatorial aspect, which is what ALSYMPCA was originally designed to do because the best standard of care was the control arm.

 

Recently, this was just presented thanks to Silk Gilessen and Bertrand Tombal at ESMO 2024 and now published in Annals of Oncology. Unlike ERA-223, the PEACE-3 trial, it is almost an exact same first-line mCRPC population looked at enzalutamide combining with radium 6 cycles, the traditional 6 cycles of radium given once a month vs just enzalutamide by itself in the approved dose.

 

[01:50:58]

 

PEACE-3: Fracture Rates by Mandating Use of BPAs With Enzalutamide ± Radium-223

 

At the end of the day, the bottom line interesting show the actually very early on the importance of using bone protective agents, bone health agents antiresorptives. This was really, really key. I think this is key to all of our patients who have any form of bone disease that they should be on a RANK ligand monoclonal antibody, or a bisphosphonate. This was really remarkable, and these curves really even show the benefit in patients on enzalutamide alone as well, the importance of a bone protective agent.

 

[01:51:32]

 

PEACE-3: rPFS and OS

 

Here the key, the KMs, the rPFS, and the OS clearly demonstrating an improvement in the combination. For so long in prostate cancer, we marched along in a monolithic way, one thing after another. I think that one of the data points that we oftentimes see is so many of our patients succumb to the disease, and they have only received one, maybe 2 life-prolonging agents. How do we correct that, do better genetic testing to see if they would benefit from a PARP inhibitor, and then just be able to have that shared decision-making conversation about a level 1 evidence where combinations clearly work? Here is an example of that that our European colleagues did for us in the EOR TC. I think this is a very important trial that is now getting into virtually all guidelines.

 

[01:52:23]

 

Key Ongoing Trials Assessing Radium-223 in mCRPC

 

Radium, which has been approved for radium-223, which has been out for over 10 years. Here is just a list and it lists of some really remarkably interesting studies. Radium followed by docetaxel, docetaxel followed by radium, combining radium and docetaxel both in reduced dose. Mike Morris is leading this. Then other examples of the sequencing of where does it apply before or after lutetium or even combining it with a checkpoint inhibitor. Again, this adds to our treasure trove of potential options for our patients. At the end of the day, as Alicia said earlier, this is the unmet need. MCRPC is a lethal disease, and how can we do better?

 

[01:53:11]

 

Evolution of PSMA-Based Radioligand Therapy Phase III Trials

 

Let us get to the RLTs. I love this slide because it really just speaks to the rapid progression of trial advancement starting with vision, which is lutetium-617 in a heavily pretreated high tumor burden group, all post-ARPI and taxane, sometimes 2 taxane, sometimes 2 ARPIs and 1-2 taxanes. That was a positive study. I will show you that KM in a second. That approval here in the United States post-chemotherapy mCRPC patients also post an ARPI led to the lutetium-617 approval here in the US which then led to these 3 other pre-chemotherapy mCRPC trials.

 

Then you see in the hormone-sensitive state, there are many more trials looking at the radioligand therapies as avoidance or delaying androgen deprivation therapy, other combinations with PARP inhibitors, and also even in the neoadjuvant space. The landscape we are going to start to see here at ASCO over the next few years, ASCO GU as well. Multiple readouts and presentations on this really exciting area.

 

[01:54:28]

 

Phase III VISION: 177Lu-PSMA-617 + SoC vs SoC Alone

 

This is just a quick recapitulation of the VISION study. This has been well presented before, published a New England journal. This was a landscape-changing RLT, the really the first one.

 

[01:54:42]

 

VISION: Efficacy of 177Lu-PSMA-617 + Best SoC in mCRPC

 

Now we have the second one with the fore. Here is the KMS on it for improving overall survival and rPFS. Really pretty dramatic leaving us with the approval by the FDA in March 23rd, 2022. Literally, 3 years ago.

 

[01:55:00]

 

PSMAfore: 177Lu-PSMA-617 vs ARPI in Taxane-Naive PSMA+ mCRPC

 

Then lo and behold, just a few months ago we had the FDA approval of the fore trial. This is in the pre chemotherapy mCRPC patient population. You can see the trial SCHEMA here, which is basically the same Q6-week 6 cycles of lutetium PSMA-617 vs the sequencing of ARPI to ENZA or ENZA to ARPI, which happens very frequently in the community despite the fact that many would argue that it is a lateral move. Everyone has their empiric anecdotal stories. However, nonetheless, this is a real-world interesting study that allowed for that. However, most importantly looked at a patient population that had not received chemotherapy in the mCRPC population.

 

[01:55:49]

 

PSMAfore: rPFS and OS

 

Here is the rPFS, the curves separate very early. One sees the delta on the median follow up as well as a hazard ratio of 0.49. Now, the OS ultimately was not statistically significant. Ultimately, in the final analysis it was fell below unity, so there was no detrimental effect. There was a greater than 50% of the patient population that was in the sequencing arm crossed over and did not also receive lutetium-617. I think on the basis of a positive VISION study, which had rPFS and OS benefit, the FDA approved this and this is now available in the US in the pre-chemotherapy space. You see this is in March 28th. This is just literally a couple of months ago.

 

[01:56:44]

 

Mechanism of Action of 177Lu-PNT2002

 

There are other studies, I am going to go through this pretty quickly just for purposes of time. This is a PNT2002. This is the SPLASH trial, a different little targeting small molecule radioligand linked to a DOTAGA radiometal chelator. At the end of the day, this was a positive study.

 

[01:57:05]

 

SPLASH: 177Lu-PNT2002 vs ARPI in mCRPC

 

They met their rPFS and here is the KM for that. Their hazard ratio 0.71, OS was immature. The company has a public release that they are not moving forward with a filing for approval for this.

 

[01:57:23]

 

SPLASH: ORR

 

Here are the objective response rates. An active drug. This drug was interesting. They have given in 4 cycles once every 8 weeks. However, at the end of the day, that drug development is not moving forward.

 

[01:57:38]

 

ECLIPSE: 177Lu-PSMA-I&T vs SoC in mCRPC

 

Here is an important study which has not yet read out yet, although the endpoint has been met on rPFS, and this is the Curium product also known as the ECLIPSE trial. Similarly, a 2:1 randomization, and this is again, almost identical schema that we saw in PSMA4 for lutetium-617. This is the Lutetium PSMA INT by Curium.

 

[01:58:05]

 

Multiple Current Pathways to the Onset of mCRPC

 

There are multiple different ways, and we talked about this earlier, how we get to mCRPC. We can get there from failing to cure high-risk localized disease. A lot of great trials coming out on that. Time is not going to allow us to go through all of that. Then we have patients who present with oligometastatic disease with low volume, high volume metastatic disease with recurrent disease. Then, of course, there is the conundrum about PSMA PET and how we think about that in comparison to conventional imaging. I think we are going to see, hopefully before the end of the year, some publication from PCWG4, which will probably almost assuredly be addressing how we think about that.

 

[01:58:53]

 

Other Targeted Radionuclide Therapeutic Approaches Under Investigation in mCRPC

 

This is just a very small list of so many other studies that are ongoing with non-beta particle. Lutetium is a small particle, relatively speaking. When you look at reader pharmaceuticals, the alpha particles tend to be much larger, do not require as much lead shielding, have a much shallower depth of penetration, but also have some different potential benefits in potency, but also have different side effect tolerability profiles. This is just listing just a mere few of the actinium studies that are out there. There are many. If you look closely on that circle, which is a great slide that Chuck showed you, take a look at that, and you will see that this is just an incredibly burgeoning field with many other important radioligand therapies.

 

Let's Revisit Our Patient Case

 

[01:59:45]

 

Patient Case: A 65-Yr-Old Man With mCRPC

 

Let us go back to our patient case, 65-year-old, mCRPC, diagnosed 2 years earlier with de novo mHSPC. Technically, I am only telling you he has had PSMA PET3 axial spine pelvic lesion, 4 bone lesions and nodal disease, but no visceral metastases. Starts on ADT and an ARPI, gets a good response 2 years later. He is now resistant. Let us assume his T is suppressed. I agree with Chuck. Extremely important to check T at baseline whenever the PSA goes up. Then has a new lesion on PSMA PET.

 

[02:00:27]

 

Posttest 4: Which of the following would you recommend as the best next step for this patient?

 

Okay. Which of the following would you recommend as the best next step for this patient?

 

1. Actinium-225;
2. Cabazitaxel;
3. Lutetium-PSMA-617; or
4. Olaparib.

 

All right. Okay. Wonderful. That is exactly right. This is all approved in the US. There are a lot of other folks are probably here from countries outside the US. A lot of folks have accessibility to some of their institutions who are able to provide this as well.

 

[02:01:15]

 

And here is the rationale for it, but I am not going to read it. I think this is really a great example of wonderful clinical trial development and more things to come. It is an exciting area, the whole RLT place.

 

[02:01:26]

 

ASCO 2025: Key Studies in mCRPC

 

Here are some key studies in mCRPC. Artificial intelligence, uber important PTEN trials, PTEN 40% presence on IHC with mCRPC patients, so actually even at higher percentage that you would typically see compared to HRR mutations. It would be interesting to see if we get a PIK3/AKT pathway, oral drug approved at some point in mCRPC. Quality of life, super important, and additional combination studies of PARP inhibitors and radium vs not.

 

[02:02:08]

 

ASCO 2025: Key Studies in Prostate Cancer

 

I think here is a few more. Looking at combinations of darolutamide. The mevrometostat was already mentioned by Alicia, and I think that EZH2 space is very, very important. There are a lot of companies that are developing EZH2 molecules. There are a lot of companies that are working on ProTax and AR degraders, and there's a lot of companies working on the ADCs. Will they all come out with the same results? Highly unlikely. Some will probably have better efficacy, some may have better tolerability just like we saw in the RLT studies.

 

A Final Survey

 

[02:02:43]

 

Poll 3: Do you plan to make any changes in your clinical practice based on what you learned in today's program?

 

Final survey. Do you plan to make any changes in your clinical practice based upon what you learned in today's program?

 

1. Yes;
2. No;
3. Uncertain.

 

All right.

 

[02:03:17]

 

Poll 4: Please take a moment to text in one key change that you plan to make in your clinical practice based on this education.

 

This is for you on your computers. Text in one key change that you plan to make in your clinical practice based on this education. We are not going to see this. This is great feedback for us here so we can think about making any potential changes for future programs.

 

Q&A

 

Dr Shore: Question and answer. There was a question earlier about using PET scan, Alicia. You got somebody who is high risk localized. I think that what they were thinking about is you get conventional imaging, it is totally negative, then you get a PSMA PET. How do you think about categorizing positive findings? Low, high, or something in the intermediate zone because you see these patients now. What do you do with those patients?

 

Dr Morgans: This is the right thing to do. Getting a PSMA PET in the high-risk localized setting is something that is guideline-endorsed. I think we routinely do that. Also, very high risk. Even some patients who have unfavorable intermediate risk, you can think about getting a PSMA PET. If we see locally advanced pelvic nodal involvement, even though the conventional imaging is negative, we tend to shift those patients away from surgery unless it is a single node that seems to be in the surgical template that the surgeon is going to take because we would then follow the STAMPEDE intensification with ADT and abiraterone for 2 years with PBRT. I think that even though that study was done with conventional imaging, we are certainly extrapolating to PSMA PET and assuming that that population can still benefit. However, this is of course an extrapolation. That is really not the data that was presented in the STAMPEDE trial. That was all conventional imaging.

 

However, when patients have metastatic disease, to your point, this is where we need to think about high and low-volume disease. If this patient has lots of lymph node involvement, technically that is a fair amount of metastatic disease, but it still would not meet criteria for high volume. We do not yet have a perfect crosswalk between PSMA PET data and conventional imaging. Really high volume, low volume is still established by conventional imaging. If everything is negative, I would be very loath to call, no matter what volume, high volume except liver. I would probably biopsy that, and I would figure out why did I not see that on my conventional imaging? Because it should really be seen.

 

Dr Shore: Chuck, for you, I know you have great access to so many of these trials, if not all because certain memorial and you presented and there was a really herculean amount of work that you presented in a very short period of time. However, tomorrow in clinic, patient comes to you and they are referred in. They had mHSPC, de novo recurrent, they come in, you are not really sure what their volume status was. Now they are mCRPC, and they have not had any treatment in first-line. They had ADT and an ARPI, and they had 4 of the 6 doses of docetaxel. Now they are T suppressed, their PSA is going up, they clearly have mCRPC, they have nodal and bone disease, no visceral metastases. What are you offering that patient?

 

Dr Ryan: Right. First of all, tomorrow in clinic I would say, sir, go home. It is Sunday, the clinic is closed.

 

Dr Shore: Good point.

 

Dr Ryan: However, after that, maybe I would see them on Monday, we would talk through the various options. Now he had 4 of 6 cycles of docetaxel in the hormone-sensitive space. We forget, I think, that we treat to the point of docetaxel-resistant in the hormone-sensitive space. That is a standard of care option that he would have. I think that going back to docetaxel remains something that frankly I would have more confidence in than going to a second ARPI. I think that that is a key thing. A lot of these studies, we talked about some of the studies that Alicia presented, have ARPI change as the control arm. Consistently, we are seeing the response proportion in that setting is 15% for a median duration of maybe 3 and a half months. You just do not get a lot of great long-term clinical benefit out of that second ARPI.

 

This patient will have the choice of going back to docetaxel. Of course, he has the option of doing a radioligand therapy, and he is on label for radioligand therapy because he is in the old label with the base on the vision trial. He is post docetaxel, but he is also in the CRPC space. He is docetaxel-naive for CRPC. Radioligand therapy would be a great choice for this patient. I forget how many lesions he has, but it is a low-volume situation. Well-tolerated therapy for him as well.

 

The final point, Neal, you talked about the PEACE-3 trial and radium 223, which is an option. However, remember, the benefits of radium are typically confined to patients with bone mets. Not typically. They are confined to patients with bone mets. The PEACE-3 trial was really remarkable because it seemed to demonstrate that you can leverage the interaction between the AR and the bone radioligand therapy. However, in this case, I just do not feel so comfortable going back to that second ARPI. This is a question I get a lot. Would you do PAECE-3 enzalutamide plus radium in this patient? I do not know what you would do, but I do not have clarity on how beneficial that would be.

 

Dr Shore: I think most of the people in PEACE-3 came in from a monotherapy ADT.

 

Dr Ryan: 3% that had received abiraterone had a result.

 

Dr Shore: I think you are spot on. Of course, I know you get genetic testing, so if the patient had an HR mutation, you would potentially be talking to them about a PARP inhibitor too, and, of course, clinical trial.