Kimberly Podsada: Thank you, Kristi. I am going to start talking about some of our other targeted therapies.

[00:56:31]

Approved PARP Inhibitors in BRCA-Mutated Breast Cancer

I will of course mention along the way some of my concerns regarding adherence, whether that is due to pill burden or whether that is due to toxicities. First of all, the 2 PARP inhibitors I am going to review are olaparib and talazoparib.

First of all, you need to have an FDA approved companion diagnostic test that demonstrates that you have a BRCA mutation. In the olaparib clinical trials, it was actually studied for metastatic and for the adjuvant setting. Very much like the CDK4/6 inhibitors that Kristi was talking about, we are seeing a lot of these drugs move into the adjuvant setting as well, and also have a really good benefit for our patients that are considered high risk.

Olaparib has taken 300 mg twice a day with and without food. In the adjuvant treatment, it is for adult patients with our deleterious or suspected deleterious germline BRCA-mutated HER2-negative high-risk early breast cancer who were treated with neoadjuvant or adjuvant chemotherapy. These are hormone positives or our triple negatives.

Then it is also same dosing for the metastatic setting. In the metastatic setting, patients are staying on this therapy until unacceptable toxicity or disease progression. In the adjuvant setting, they are taking it for 12 months. Also in the adjuvant setting, what is important to think about are we are really giving it to a specific patient population who are at high risk. In the adjuvant setting clinical trial, we did see a clinically meaningful overall survival as well as a disease risk reduction of recurrence. So it is making a difference in the adjuvant setting.

Although I am not going to go into too many details about the clinical trials, please know that we are talking about these therapies and recommending these therapies because it has shown to be better than that standard of care or chemotherapy. It is also allowing patients to stay on oral therapies before needing another line of chemotherapy.

Talazoparib is 1 mg once a day with or without food, again, needing to have that germline BRCA-mutated FDA-approved companion diagnostic test.

[00:59:11]

PARP Inhibitors: MoA

I am going to do a very simplified version of a PARP inhibitor mechanism of action. This is important for me to understand because when I explained this to my patient, Kristi was really, really, really good at making sure we are educating our patients. Sometimes I will let them know about the mechanism of action as well. I will give them visuals maybe to think about adherence and why they are on something and why a medication is working.

If you think about this BRCA mutation, it is something that is genetically passed on to an individual. This is in their DNA. There is a mutation that the body is constantly repairing. PARP genes encode for this enzyme that help to maintain DNA integrity. If you imagine that you have got this mutation in your DNA and PARP is constantly coming in and repairing it like its normal job, because it sees it as being something normal.

This damage is constantly being repaired. By applying a PARP inhibitor, we are stopping that process. We are stopping that mutation from continuing to proliferate. This then causes apoptosis for these breast cancer cells in patients who are BRCA positive. That is my simplified version.

[01:00:52]

Differences Between Somatic and Germine Mutations

When we think about our mutations, we are looking at germline or somatic mutation. The germline is where it is inherited, mom or dad or grandmother or grandfather. It has been passed down through the family, whether or not those individuals actually had breast cancer or other cancers, you have a 50% chance of getting this mutation. Just because you have the mutation does not mean that you are going to have a breast cancer and other cancer, but you are much higher risk of it happening.

Then we have our somatic mutations and these are acquired. This is the actual cancer cell itself that becomes mutated and acquires this mutation. It is important to always constantly be thinking about repeat testing to see if there are new targetable mutations that are available for these therapies.

[01:01:54]

PARP Inhibitors: Tolerance Profiles of Olaparib and Talazoparib

Looking at some of the PARP inhibitor AEs that grade 3 AE is really where you are going to need to intervene and help your patient manage this. We have the abnormal labs, especially anemia. Anemia is going to be significant, which then may contribute to fatigue as well. We have to think about maybe giving our patients some tips and tools on how to manage fatigue. Anemia, we are going to catch by blood work, which we are going to be doing frequently.

Also, both of these PARP inhibitors had neutropenia and thrombocytopenia. Labs are going to be done regularly, typically monthly, and as indicated. Now, MDS and AML were seen using these PARP inhibitors for the olaparib studies, there were no signs of MDS or AML, but if you find that your patients’ counts are not recovering well, you are continuing to run into issues, you may want to have a hematologist consult.

For all grades nausea, you can see both PARP inhibitors are going to have nausea as something that we also need to help manage, and alopecia as well, although alopecia was more of a grade 1 with just some hair thinning.

[01:03:26]

Managing GI Toxicity With PARP Inhibitors

GI toxicity is probably 1 of the main concerns with the PARP inhibitors. Even with mild nausea and vomiting, this may affect the patient's adherence because it does impact the quality of life. But nausea and vomiting tend to diminish over time. Using prophylactic medication usually in the beginning is very helpful. Letting them know that they may want to take an antiemetic before each PARP inhibitor and twice a day with olaparib.

You want to avoid aprepitant with olaparib because, again, we need to know those other drugs and the interactions. You can also recommend taking PARP inhibitor after meals to reduce nausea as well. It is not likely that they are going to have severe nausea and vomiting, so you do want to be thoughtful about working up other things if this continues. Then, of course, other GI toxicities, constipation, diarrhea, and abdominal pain.

[01:04:31]

Managing PARP Inhibitor–Associated Nonhematologic Toxicities

As with many grading and trying to figure out how to best help patients manage toxicities that grade 1, grade 2, sometimes you do not need to intervene, but maybe you want to look at nutrition, make some recommendations. For those grade 2s, you may need to hold their dose or dose reduce.

[01:04:55]

Recognition, Prevention, and Management of Common AEs Related to PARP Inhibitors

Again, when we looked at some of the AEs here, we can see abnormal labs are very common with both PARP inhibitors that nausea, anemia, and fatigue as well. These are things that may be challenging for your patient to adhere to the medication regimens.

[01:05:15]

Skill Building and Feedback II (ARS/Case Discussion): Class-Specific Barriers to Adherence and Persistence, Patient Counseling, and AE Management for PARP Inhibitors

For this patient, Kristi and I are going to discuss a 36-year-old woman who was diagnosed with high-risk, early-stage, BRCA1, left breast cancer, who completed all of her chemotherapy, underwent bilateral mastectomies, radiation, and then she started on her GnRH agonist injections monthly with her anastrozole and olaparib twice a day.

She and her husband have 2 children. They are young, 3 and 6. She works part-time, he works full-time and she is reporting bothersome fatigue and nausea and admits to occasionally missing her second dose of olaparib.

First of all, what are some of the other symptoms we might work up and how are we working up her symptoms, like looking at those labs? What interventions would we consider and how would we advise her to consistently take her scheduled doses of medications? Do not forget that you can use the question and answer box if you want to add your 2 cents, which we would appreciate.

Kristi, what do you do in this situation? We only have a couple of minutes, but I would love to hear your take on this.

Kristi Orbaugh: We hit earlier on the fatigue and such, and obviously the last thing we want her to do is to miss any pills, right? If we can avoid that. Maybe even scheduling antiemetics, so she is taking them regularly and hopefully that would mitigate some of that.

Kimberly Podsada: Thank you, Stephanie, for writing in. She thinks this woman needs a nanny. Yes, she needs more support for sure. We have to look at the whole patient and she is busy. Her husband is busy. We want to help her make sure she can stay on this therapy. Again, it has demonstrated overall survival. She is high risk. It is demonstrated reducing the risk of disease recurrence.

We have to think about what is going to work best for her and incorporate some of the tools that Kristi discussed.

Kristi Orbaugh: Kimberly, when we are working up her symptoms, take away her breast cancer, okay, forget her breast cancer and look at where she is in life. She is fatigued anyway, most likely. We also have to make sure that when we are setting with patients and we are really assessing them, sometimes we have to pull away the noise. Part of that may be, just helping her maybe understand better energy conservation strategies and such. The poor gal, she has got a lot of balls in the air and she would be tired whether she were taking medications that could make her fatigued or not. So helping support her through that.

Kimberly Podsada: Yes, and Dorothy also mentions here that sometimes the psychology of a patient feeling like they are a burden, it can be very overwhelming. We need to encourage her as well as other patients to really allow friends and family to help and setting an alarm also on her phone or something for that having to take a medication twice a day.

I am going to move on. Thank you.

[01:09:10]

HER2-Targeted TKIs

I am going to talk about the HER2-targeted TKIs, or tyrosine kinase inhibitors.

[01:09:17]

Approved HER2-Targeted TKIs

We have 3 that are currently approved for HER2-targeted TKIs in the breast cancer world. Neratinib, again, is used in the adjuvant setting as well as the metastatic setting. One of the challenges that people may have with neratinib is it is 6 pills, but it is only once a day. It usually is with their endocrine therapy as well. In the metastatic setting, it is also taken with capecitabine, which also can be pill heavy.

Neratinib is taken daily, whereas capecitabine is taken for your 2 weeks on and 1 week off. Definitely need to make sure patients have resources to remember that schedule.

Tucatinib is given with trastuzumab and capecitabine, and this is for HER2-positive breast cancer, including brain mets for those patients who received 1 or more greater lines of HER2-targeted therapies. This medication is given twice a day, but the capecitabine is also given twice a day. Those 2 medications can be taken at the same time. Remembering that capecitabine is still 2 weeks on and 1 week off, and tucatinib is daily.

Then we have lapatinib. It is also approved in the metastatic setting and it is used with capecitabine as well, or it is used with letrozole. Again, we need to think about some of the pill burden here, especially for lapatinib, which also is 6 pills at once as well.

[01:10:59]

HER2-Targeted TKIs

Simplified graft here, really showing you the targets of each of these TKIs. You can see here that the neratinib is hitting several HER receptors. We have 4 HER receptors and neratinib is hitting the majority of them, which is known to potentially increase some of the side effects that it has. Whereas lapatinib and tucatinib are very highly specific and have less side effects than the neratinib does.

[01:11:35]

Pharmacology of HER2-Targeted TKIs

There is also different inhibitions. Lapatinib and tucatinib are also reversible as well as more highly selective than neratinib. But the neratinib is also the only 1 that has been approved in the adjuvant setting. Again, watch what other drugs that your patient is taking because it is also metabolized by the CYP3A receptor in the liver.

[01:12:01]

Recognition, Prevention, and Management of Common AEs With HER2-TKIs

All 3 of the TKIs, we need to pay attention to diarrhea, nausea, vomiting, fatigue sometimes rash, sometimes mouth sores. We need to rule out other possible causes of diarrhea. We want to be aggressive with our antidiarrheals as scheduled or as needed.

Loperamide, Lomotil, budesonide, colestipol followed by potential dose reduction as needed. Also there is a really interesting study called the CONTROL study, where it looked at dose escalation of neratinib. This has really helped to mitigate some of the diarrhea for patients with neratinib.

[01:12:49]

Considerations for Management of Neratinib-Induced Diarrhea: Prophylaxis

Considering our management of diarrhea, we can do that dose escalation, which has been very helpful. We can start off immediately with the loperamide. You can have patients just start automatically taking it and not waiting till they have diarrhea. Then we also want to think about doing dose reductions, if we need to as well or permanently discontinuing for grade 4 diarrhea or more.

[01:13:22]

Skill Building and Feedback III (ARS/Case Discussion): Class-Specific Barriers to Adherence and Persistence, Patient Counseling, and AE Management for HER2-Targeted Therapy

Now I am going to bring back Kristi to talk with me about some symptom management for a TKI. We have a 55-year-old woman who is diagnosed with locally advanced right hormone-positive, HER2-positive breast cancer. She completed neoadjuvant chemotherapy, including her HER2-directed therapy. She had residual disease at the time of surgery and went on to complete a full year of HER2-directed therapy.

After surgery and radiation, however, she started her letrozole daily. After completing her HER2-directed infusion, she was started on adjuvant neratinib 240 mg daily to complete 1 full year of treatment. She informs you that she has concerns about starting because she has diarrhea and continues to have irregular bowels since chemotherapy.

Kristi, what options would you discuss with her to mitigate bothersome diarrhea and what additional supportive interventions would you recommend?

Kristi Orbaugh: My husband probably just wishes I would mute myself probably. When I use neratinib, I have had occasion in patients where I will actually start at a lower dose and then escalate up. She is definitely someone that I would get on Imodium on a regular basis before she ever took the first 1 or Lomotil or colestipol. I have also in this sort of situation had some really good results with bulk forming agents in patients when I am starting them out and starting to escalate that dose.

Kimberly Podsada: Yeah, I have found again that once someone finds what works best for them they just stick with it. Again, I have a lot of patients who will find they need 1 Imodium maybe twice a day, and that is what they take and they continue to have a normal bowel movement every day. Again, it is just finding what works best for that patient.

Thank you for the comments. I am going to move on to our next section. Please feel free to use the question and answer chat box.

[01:15:57]

PI3K, AKT, & mTOR Inhibitors

Okay. I am going to talk about our PI3 kinase, AKT and mTOR inhibitors.

[01:16:07]

Approved PI3K/AKT/mTOR Inhibitors for HR+ MBC

Currently, we have approval for several therapies, which is very exciting. Everolimus was the first-to-market, and it is considered an mTOR inhibitor. You do not need a test that shows that you have 1 of these mutations. Everolimus is taken 10 mg orally once daily. These are for hormone-positive breast cancer patients. They are also going to continue on their endocrine therapy.

Alpelisib, you need to have a confirmed test of a PIK3CA mutation. It is taken 300 mg orally once daily with food as well as your endocrine therapy.

Capivasertib is also approved. Interestingly, it is the first 1 that has been approved for an AKT1 mutation. You definitely want to have your test that shows there is a mutation within the PIK3CA, AKT1 or PTEN. It is 400 mg. It is 2 tablets taken twice a day with or without food. It is an interesting schedule. It is 4 days on, followed by 3 days off. They found that this did help with tolerability.

Then we have inavolisib. It is a 9-mg orally once a day with or without food. Again, this is specific for patients with a PIK3CA mutation.

[01:17:47]

Combining Targeted and Antiestrogen Therapies to Overcome Resistance in HR+ Advanced Breast Cancer

Although this is busy, this is such an informative slide. I would not spend all day going through this because it is a lot. But it really gives you that good overview of where a lot of the therapies we have discussed, how they interact. We have the extracellular activity and then we have our intercellular activity. We have those extracellular triggers that then create this cascade pathway where we see our PI3 kinase, AKT, mTOR pathway then activated, and where we have our inhibitors that targeted.

When we are looking at a lot of these, we want to have additional therapies now that we can offer patients to target these areas where we really find a lot of endocrine resistance is developing. Now we have these more targeted therapies to overcome that resistance.

[01:18:49]

Indications for PI3K/AKT/mTOR Inhibitors

Now the majority of these therapies are approved in postmenopausal women or if they are pre or perimenopausal, then they are going to go on to ovarian suppression. You need a testing that confirms that you do have a mutation. For alpelisib and inavolisib, it is that PIK3CA mutation. For capivasertib, you can have a PIK3CA mutation, but it also is an AKT1 or a PTEN alteration that you may also use capivasertib in.

[01:19:27]

Key AEs With PI3K/AKT/mTOR Inhibitors: Monitoring and Prevention to Maximize Adherence

Here you can see that all 3 of these TKIs will have diarrhea to some degree, stomatitis and hyperglycemia. The hyperglycemia I think has been probably the steepest learning curve for a lot of people. We have gotten a little more comfortable with it if you have used alpelisib since that came to market a few years ago. But it is definitely something we have to pay close attention to.

You are not giving someone diabetes, but it is hyperglycemia. We do use medications often that we treat diabetes with. You really need to follow closely the fasting glucose, the hemoglobin A1C, and then you want to optimize the blood glucose before starting treatment. If they have preexisting conditions and they are a prediabetic, you pretty much want to get the endocrinologist involved and start them on something before starting 1 of these medications.

You will be checking labs sometimes twice a week for 4 weeks, or you may do every week times 2, and then every 2 weeks. Because this is so prevalent, a lot of the providers that I even work with will go above and beyond with blood work because they really want to capture this early on to get the best dose and the safest dose for the patient.

[01:21:00]

Skill Building and Feedback IV (ARS/Case Discussions): Class-Specific Barriers to Adherence and Persistence, Patient Counseling, and AE Management for PI3K Inhibitors

Okay, now we are going to spend some time looking at this patient. Kristi is going to be welcomed back to talk with us about this 68-year-old woman who was diagnosed with de novo hormone-positive, HER2-negative metastatic breast cancer. She completed her first-line of therapy with ribociclib and an AI.

At the time of disease progression, she had a ctDNA test that revealed a PIK3CA mutation, and she was started on alpelisib 300 mg daily with fulvestrant. Her baseline characteristics include an elevated blood serum glucose, hemoglobin A1C is 6, BMI is greater than 30. She has intermittent elevated LFTs while she was on her CDK4/6 inhibitor in AI and neutropenia.

What would you do to reduce her risk of worsening hyperglycemia? What symptoms would you ask her report to the care team? Are there other symptom risk reduction strategies you would advise? Again, please feel free to use your question and answer box.

Kristi, what do you think?

Kristi Orbaugh: Well, I will tell you, this is someone that obviously is already comes to us with hyperglycemia. She has got various risk factors that put her at higher risk. I would phone a friend. We are very blessed at the area I work in. We have a wonderful endocrinologist that actually works in our clinic on every Monday. If you do not have an endocrinologist, I realize sometimes those are like finding a unicorn. Sometimes they are difficult to find. But also reach out to her PCP if they have previously been managing this hyperglycemia.

This would be a challenge with this patient I would think. Not one that we cannot overcome, but certainly one that is going to take a very aggressive healthcare team.

Kimberly Podsada: Right. I think a lot of the providers that I work with are also very comfortable managing metformin now. This is someone who I would consider upfront ordering metformin for and then having her see 1 of our registered dieticians as well. Think about ways to help her improve these numbers through her nutrition as well as through medication. An endocrinologist would also be great, hoping she already has someone.

Okay. Anything else you want to add to that?

Kristi Orbaugh: No. I think we talked about the appropriate signs and symptoms to report to the healthcare team. Clearly, increased thirst, increased urination, lightheadedness, dizziness, all of those things, we would have covered with her.

Kimberly Podsada: One of the things that I also really talk with patients about are expectations. I will let them know that this is a potential, it is highly likely, especially given her situation, and really just encourage her to work with us for the first few months, maybe only a couple of months. But once you find the right dose and the right interventions and medications, this can be very tolerable. You can make this happen.

Again, I think just those realistic expectations would also help. Yes, and the glucometer. Our office is also now prescribing glucometers so that they can have easy access at home for checking their blood sugars. When we talk about access to care what can we make sure patients have at home, so they are not coming in so frequently, maybe for those blood draws or they can check it at home. Then let us know what their numbers are.