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Incorporating PARP Inhibitors for mCRPC: A Nursing Perspective
Incorporating PARP Inhibitors for mCRPC: A Nursing Perspective

Released: May 31, 2022

Expiration: May 30, 2023

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Prostate cancer is the most frequently diagnosed malignancy in men and the second-leading cause of cancer-related deaths. Overall survival is significantly reduced for men with metastatic castration-resistant prostate cancer (mCRPC), so additional therapies are needed in this setting. Numerous additional therapies have been approved in prostate cancer recently, and they are extending the overall survival of patients.

PARP refers to several enzymes involved in single-stranded DNA repair. BRCA1 and 2 are proteins involved in homologous DNA repair, and mutations in BRCA1/2 confer sensitivity to PARP inhibitors. Some gene mutations in other DNA repair genes also improve sensitivity to PARP inhibition, and approximately 12% of all prostate cancers contain 1 of these mutations. These may be inherited germline mutations or somatic mutations within the tumor. Germline mutations in BRCA1/2 increase a person’s risk of developing certain types of cancer. Currently, PARP inhibitors are approved by the FDA for breast, ovarian, pancreatic, and prostate cancers.

Genetic and Molecular Testing

Consideration of genetic testing should be a part of the diagnostic workup. It is important to ask about family history of cancer to help determine if a patient should receive germline testing. Patients considering or receiving germline testing also should meet with a genetic counselor, as the results can impact other family members. Guidelines recommend that patients with prostate cancer and a family history of certain cancers or other relevant factors receive germline testing. It also is recommended that all patients with metastatic prostate cancer have somatic tumor testing for BRCA1/2 mutations. It is important to understand which test is needed and order the correct one. Multigene panels using next-generation sequencing are preferred to maximize the amount of information obtained while minimizing the amount of tissue needed.

Approved PARP Inhibitors for mCRPC

Clinical Evidence

Currently, 2 PARP inhibitors are approved for use in the setting of mCRPC—olaparib and rucaparib. Their approved indications are different, and it is important to understand those differences. Rucaparib is approved for adults with deleterious BRCA mutation (germline or somatic)–associated mCRPC who have received androgen receptor–directed therapy and taxane-based chemotherapy. Patients are selected using an FDA-approved companion diagnostic. Rucaparib has an accelerated approval based on the phase II Triton2 trial, which showed an overall response rate of 43.5% in patients receiving rucaparib. Olaparib has a broader indication in terms of the types of tumor mutations because the phase III PROfound trial enrolled patients with mutations in 15 different genes involved in homologous recombination repair (HRR) and was a positive trial. This trial found that olaparib significantly improved median progression-free survival (PFS) vs physician’s choice of therapy (7.4 months vs 3.6 months, respectively). This led to approval of olaparib for adult patients with deleterious or suspected deleterious germline or somatic HRR gene-mutated mCRPC who have progressed following prior treatment with enzalutamide or abiraterone. Again, patient selection is based on an FDA-approved companion diagnostic. So, patients with mutations in genes other than BRCA may benefit from olaparib, and they do not need to have a history of taxane treatment before use.

Dosing and Adverse Events (AEs)

Both olaparib and rucaparib are oral therapies available in different dose tablets. The starting dose of olaparib is 300 mg twice daily, and for rucaparib the starting dose is 600 mg twice daily. For patients receiving olaparib, it is important to counsel them to avoid grapefruit and Seville oranges, as these may increase the amount of the drug in the blood. Healthcare professionals also should be aware of the potential for interactions with CYP3A inhibitors and reduce olaparib dosage according to the prescribing information. Patients with renal impairment receiving olaparib may need a dose reduction based on the level of impairment.

As a class, PARP inhibitors have similar AE profiles, with fatigue, nausea, diarrhea, vomiting, and cytopenias being common. Anemia is the most common grade ≥3 AE seen with either therapy. Differences in AE profile between olaparib and rucaparib include cough, dyspnea, venous thromboembolism, and pneumonitis with olaparib vs rash and increased aspartate aminotransferase and alanine aminotransferase with rucaparib. Both agents carry a rare incidence of myelodysplastic syndromes, which is something to consider for younger patients who may receive a PARP inhibitor for a longer period of time. AEs can be managed with dose reductions and dose holds, along with appropriate monitoring and prophylactic measures. Remember to educate your patients about AEs to be aware of and about dose holds and dose reductions when you initiate PARP inhibitor therapy.

Gastrointestinal (GI) AEs

Prophylactic antidiarrheals such as loperamide should be taken prior to the PARP inhibitor to minimize GI AEs. It is important to note that aprepitant should not be used with olaparib because of a CYP3A4 interaction. It is also helpful to take PARP inhibitors with food. Educate patients that if they vomit shortly after taking their PARP inhibitor, they should not take an additional dose.

Cytopenias

Monthly complete blood counts with differential should be standard-of-care monitoring for patients receiving PARP inhibitors. If a patient is anemic, other causes of anemia should be ruled out. For grade ≥3 anemia, hold the PARP inhibitor until the anemia resolves to grade ≤1, then resume at the next-lower dose. For grade 2 anemia, a dose hold can be considered. Transfusions may be necessary in cases of grade ≥3 anemia.

Future Directions

PARP inhibitors also are being examined in conjunction with second-generation androgen receptor–targeted therapies such as abiraterone acetate as first-line therapy. Two recent phase III trials reported positive outcomes with combinations: the PROpel trial of olaparib plus abiraterone/prednisone and the MAGNITUDE trial of niraparib plus abiraterone/prednisone. In the PROpel trial, a significantly improved PFS was demonstrated for all patients regardless of mutational status, but in the MAGNITUDE trial, a significant PFS benefit was observed only for patients with BRCA1/2 mutations. Two other phase III trials are ongoing evaluating rucaparib plus enzalutamide (CASPAR) and talazoparib plus enzalutamide (TALAPRO-2).

Summary

PARP inhibitors are an option for patients with mCRPC and HRR gene mutations, and there are several key points for healthcare professionals to remember.

  • Obtain family history and order germline testing if indicated by current guidelines. 
  • Order somatic testing for all patients with metastatic prostate cancer.
  • Understand the differences in indications for the approved PARP inhibitors olaparib and rucaparib. 
  • Incorporate dose holds, dose reductions, appropriate monitoring, and mitigation strategies to minimize AEs associated with PARP inhibitors, including anemia, GI toxicities, and fatigue.