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PARPi in Prostate Cancer
Understanding the Role of PARP Inhibitors in Prostate Cancer: Key Takeaways From a Symposium in San Francisco

Released: February 12, 2024

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Key Takeaways
  • PARP inhibitors are now an integral part of the treatment armamentarium, both as monotherapy and in combination with androgen receptor pathway‒targeting agents.
  • Germline and somatic testing for HRR mutations is important for patients with metastatic castration-resistant prostate cancer to determine eligibility for PARP inhibitor therapy.
  • Anemia is an important class effect associated with PARP inhibitors, and patients receiving PARP inhibitors should be monitored closely.

In this commentary derived from a recent live presentation, Andrew Armstrong, MD, ScM, FACP; Tanya B. Dorff, MD; and Neeraj Agarwal, MD, FASCO, summarize key points to consider when incorporating PARP inhibitors into clinical practice for the optimal care of patients with metastatic castration-resistant prostate cancer (mCRPC).

PARP Inhibitor Monotherapy

Andrew Armstrong, MD, ScM, FACP:
The current median overall survival (OS) for mCRPC is less than 3 years, and although many therapies are available for mCRPC, they offer only small benefits in OS. In addition, many patients do not live long enough or have sufficient performance status to receive multiple lines of therapy. Thus, there is an ongoing need for therapies to improve OS for patients with mCRPC.

The phase III PROfound trial provided level 1 evidence for olaparib, demonstrating improved OS vs physician’s choice of therapy in patients in patients with mCRPC and homologous recombination repair (HRR) mutations whose disease had progressed after novel hormonal therapy (NHT). The phase III TRITON3 trial found superior efficacy for PARP inhibition with rucaparib vs docetaxel in patients with BRCA2 mutations. Based on these 2 studies, olaparib is approved for mCRPC after NHT, and rucaparib is indicated for mCRPC after NHT and a taxane. PARP inhibitors share some adverse events because of a class effect including anemia, gastrointestinal events, and fatigue. Patients receiving PARP inhibitors should be followed carefully for anemia that may require transfusion support.

Given the availability of PARP inhibitors, it is important to perform germline and tumor or ctDNA testing, which can lead to identification of patients with an HRR deficiency, including BRCA mutations, who may benefit from PARP inhibitor monotherapy.

Rationale for Combining PARP Inhibitors With Androgen Receptor Pathway‒Targeting Therapies

Tanya B. Dorff, MD:
PARP monotherapy is effective for a subset of patients with mCRPC, but there is a desire to potentially expand the population who may benefit from PARP inhibition. Preclinical evidence supports combining PARP inhibitors with NHT targeting the androgen receptor (AR) pathway, such as enzalutamide or abiraterone acetate.

There is crosstalk between the AR signaling pathway and the DNA damage repair pathways that include PARP. PARP inhibition reduces the transcription of androgen-regulated genes, and we know that those genes are a main driver of prostate cancer progression. So, there is synergy by suppressing those genes. The converse also is true—that when you inhibit the AR pathway, some DNA repair genes are downregulated, potentially making the cell more susceptible via synthetic lethality. In my view, these data are strong preclinical rationale as to why there is synergy and why we should be using these drugs together. Even if they are not synergistic, we know that AR pathway inhibitors do not kill all cancer cells, and there is interest in PARP inhibitors being able to target resistant clones.

Efficacy and Safety of PARP Inhibitor/NHT Combinations

Neeraj Agarwal, MD, FASCO:
Three different PARP inhibitor/NHT combinations now have regulatory approval in the setting of first-line therapy for mCRPC based on phase III evidence and are part of the armamentarium for prostate cancer.

  • PROpel trial: Olaparib is indicated in combination with abiraterone and prednisone or prednisolone for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated mCRPC.
    • Olaparib plus abiraterone/prednisone improved OS in patients with BRCA mutations.
  • MAGNITUDE trial: The combination of niraparib, a PARP inhibitor, and abiraterone acetate, a CYP17 inhibitor, is indicated with prednisone for the treatment of adult patients with deleterious or suspected deleterious BRCA-mutated mCRPC.
    • Niraparib plus abiraterone/prednisone demonstrated improved radiographic progression-free survival in patients with BRCA mutations and is available as a single pill.
  • TALAPRO-2 trial: Talazoparib is indicated in combination with enzalutamide for the treatment of adult patients with HRR gene–mutated mCRPC.
    • Talazoparib plus enzalutamide met the primary endpoint of radiographic progression-free survival in the all-comer cohort and is the only combination approved for patients with non-BRCA HRR mutations.

Evidence from the phase II BRCAAway trial presented at ASCO GU 2024 suggests that a PARP inhibitor/NHT combination is superior to sequential use of these therapies. When I assess all of the evidence, there is no doubt in my mind that combination therapy should be considered for patients with newly diagnosed mCRPC with BRCA1, BRCA2, or non-BRCA HRR mutations.

Selecting Between the Approved Combinations for Patients With BRCA Mutations

Andrew Armstrong, MD, ScM, FACP:
I first pick the NHT that I plan to use, which is based on costs, drug interactions, and comorbidities. For example, I prefer abiraterone/prednisone for a patient who might be older, frail, at risk of falls, or who might have cognitive problems because enzalutamide can exacerbate those issues and because of the high level of drug interactions with enzalutamide. In a younger, healthier patient, I might pick enzalutamide. In patients with diabetes, insulin insensitivity, metabolic syndrome, or obesity; patients who have a steroid contraindication; or patients with heart failure, I do not like abiraterone/prednisone for these patients because there is the potential for more adverse events. After you select the optimal NHT for your patient, then I select the PARP inhibitor that goes with that NHT.

Tanya B. Dorff, MD:
As a reminder, we cannot mix and match any NHT with any PARP inhibitor because there are potential drug–drug interactions. We need to use approved combinations.

Andrew Armstrong, MD, ScM, FACP:
The only caveat to this strategy is that we have only 1 combination with level 1 evidence for survival, and that is olaparib plus abiraterone/prednisone. I would say that is probably the strongest evidence in patients with BRCA2 mutations. The data with talazoparib/enzalutamide are impressive for BRCA2 mutations, but we do not have mature survival data yet.

Neeraj Agarwal, MD, FASCO:
All of these considerations come into play in our regular clinics. I also choose the NHT first and then look at the PARP inhibitor partner.

Your thoughts?
In your current clinical practice, how are you incorporating PARP inhibitors into the care of patients with mCRPC? Answer the polling question and join the conversation in the discussion box below.

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