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PARPi for Advanced Prostate Cancer
PARP Inhibitors for Advanced Prostate Cancer: Global Opportunities and Challenges

Released: July 11, 2024

Expiration: July 10, 2025

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Key Takeaways
  • Molecular testing for homologous recombination repair gene mutations is critical to guide application of PARP inhibitor–based therapy and optimize outcomes for patients with advanced prostate cancer.
  • Choice of a specific androgen receptor pathway inhibitor plus PARP inhibitor combination regimen should consider previous therapy, disease characteristics, tumor molecular profile, and patient comorbidities
  • PARP inhibitors are most commonly associated with gastrointestinal toxicity and anemia and regular monitoring is needed for adverse events, particularly in the first 3-4 months

In this commentary derived from a live presentation, Karim Fizazi, MD, PhD, and Joaquin Mateo, MD, PhD, discuss key considerations and challenges when incorporating PARP inhibitors into clinical practice for the optimal care of patients with metastatic castration-resistant prostate cancer (mCRPC).

Molecular Diagnostic Testing Recommendations for Defective DNA Repair Alterations

Joaquin Mateo, MD, PhD:
Molecular diagnostic testing to identify patients with advanced prostate cancer and actionable homologous recombination repair (HRR) mutations is recommended by multiple guidelines from different medical organizations. It is important to perform both tumor/somatic tissue testing and germline testing for these patients, with the former testing informing treatment decisions and patient prognosis and the latter additionally informing the potential cascade testing of family members for increased risk of cancer. Although specific recommendations vary across available guidelines, generally broad-panel next-generation sequencing platforms are preferred with assessment of BRCA1, BRCA2, CDK12, and PALB2 capturing most patients who may benefit from PARP inhibitor therapy. Of note, fresh or archival biopsy tissue samples are both appropriate sources to use for this testing. Healthcare professionals should coordinate care across a multidisciplinary team to establish processes to ensure that patients with advanced prostate cancer are evaluated in a timely manner for HRR mutations and that patients are educated about the importance and potential implications of the testing results to their care.

PARP Inhibitors for Prostate Cancer

Karim Fizazi, MD, PhD:
Patients with newly diagnosed mCRPC and select HRR mutations may be candidates for approved combination therapy regimens with PARP inhibitors and androgen receptor pathway inhibitors (ARPI) based on evidence from 3 key trials—MAGNITUDE (niraparib and abiraterone), PROPEL (olaparib and abiraterone), and TALAPRO-2 (talazoparib and enzalutamide)—that all showed significant improvements in outcomes for these patients. Factors that affect the choice of these combination regimens for individual patients include previous therapy, disease characteristics, and patient comorbidities. In addition, olaparib and rucaparib are approved as monotherapy for patients with mCRPC and select HRR mutations who progressed on previous therapy including an ARPI based on the phase III PROfound and TRITON3 trials, respectively. At this time, there are only very preliminary data from the BRCAAway trial looking at combination therapy vs sequential therapy with ARPI and PARP inhibitors for patients with newly diagnosed mCRPC. Given the very limited data to assist with treatment decisions for combination therapy or sequential therapy at this time, clinical judgement and shared decision-making with the patient and their caregivers are essential.

Joaquin Mateo, MD, PhD:
Professor Fizazi, what are your thoughts on treatment for a patient with a BRCA mutation if a PARP inhibitor is not available?

Karim Fizazi, MD, PhD:
If PARP inhibitors are not reimbursed and simply not available at all, then for a patient with advanced disease all of the other approved standard therapies that the patient has not previously received remain options. I would also consider a platinum drug as an alternative because we have seen efficacy in these patients, although with a much lower level of available evidence than we have for PARP inhibitors. One other anecdotal observation related to platinum agents that I would like to mention is that we have tried to treat patients progressing on PARP inhibitor therapy with platins. Unfortunately, among approximately 15 such patients, I have seen only 1 response after failure of a PARP inhibitor, which suggests that cross-resistance between PARP inhibitor and platin drugs is likely to be high.

Clinical Pearls for PARP Inhibitor Adverse Event Management

Joaquin Mateo, MD, PhD:
PARP inhibitors are most commonly associated with gastrointestinal toxicity and anemia and regular monitoring is needed for adverse events, particularly in the first 3-4 months. Typically, the gastrointestinal adverse effects are well managed using either antiemetic drugs or antidiarrheal drugs or, if needed, dose reduction of the PARP inhibitor. In my practice, I have rarely needed to dose reduce a PARP inhibitor because of gastrointestinal toxicity. Something that is a bit counterintuitive related to the gastrointestinal adverse effects, but that we need to be aware of, is that it is recommended to give these drugs with food. This is because giving PARP inhibitors together with food slows down the drug absorption and that reduces the nausea feeling. So even if a patient says, “Oh, I'm a bit sick, and I don't want to eat," tell them, “If you eat a small bit with a PARP inhibitor, it may actually help your nausea.”

Anemia is a more serious issue. Transfusions are commonly needed with recent trials reporting up to 30% to 40% of patients requiring transfusions. For patients with anemia, hold the PARP inhibitor to give the patient a break and restart when the hemoglobin level is >9 g/dL. If the patient is not symptomatic with either grade 1 or 2 anemia, I generally try to restart at the same dose one time, and if anemia recurs, I will then reduce the dose. If the patient is very symptomatic or has grade 3 anemia, I will reduce the dose of the PARP inhibitor from the very first event when restarting. However, I always give the patient a break of 1-2 weeks to allow the bone marrow to recover before restarting the PARP inhibitor at the lower dose. Many patients who are benefiting from a PARP inhibitor will continue to benefit with a dose reduction. It is important that we prioritize the safety of the patient and the long-term tolerability of the drug.

Karim Fizazi, MD, PhD:
It is also important to pay attention to thromboembolic events, which are also associated with PARP inhibitors. Often thromboembolic events are detected on CT scans. Let me provide an example of a small pulmonary embolism that is detected on a CT scan and that is completely asymptomatic. In this case, in a responding patient, I would feel comfortable holding the PARP inhibitor, treating the patient with an anticoagulant, and then restarting the PARP inhibitor in 3-4 weeks, especially if a repeat CT scan shows improvement.

Joaquin Mateo, MD, PhD:
I agree and will add that most patients receiving PARP inhibitors experiencing thromboembolic events are asymptomatic. As a final general comment, the original studies of PARP inhibitors demonstrated that dose matters, with higher doses associated with higher response rates. So, we always have to start with the approved dose, but in the event of adverse events, there is room for adjustments to keep the patient on drug if he is benefiting from therapy. It is important to work with patients and monitor these events closely to find the dose that provides efficacy while maintaining tolerability.

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