APCCC 2022: Debate: PARP Inhibitors for All mCRPC Patients

(UroToday.com) In the session of the 2022 Advanced Prostate Cancer Consensus Conference focusing on the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC), Dr. Noel Clarke and Dr. Johann de Bono debated the role of PARP inhibitors for mCRPC patients. Dr. Clarke began by discussing a role for PARP inhibitors for all patients with mCRPC.

Dr. Clarke began by highlighting data from PROfound which demonstrated that olaparib is clearly an active agent in advanced prostate cancer. However, we know that its benefits are limited to a biomarker selected subset. Using a slide presented by Dr. Fred Saad at GU-ASCO 2022, Dr. Clarke emphasized that the potential synergy between olaparib and abiraterone may allow this combined treatment approach to be active in a larger subset of men. In particular, postulated mechanisms include PARP-induced androgen-receptor dependent transcription which would increase sensitivity to abiraterone and abiraterone-induced homologous recombination repair deficiency (so-called “BRCA-ness”) which would sensitize to PARP inhibition.

Stepping back, Dr. Clarke highlighted data from study-8, a large phase II trial of unselected and heavily pre-treated patients with mCRPC. Published in Lancet Oncology, these data showed a benefit of the combined approach, independent of HRR mutation status. It was these data that led to the design of the phase III PROpel trial which moved this treatment approach earlier in the natural history of disease to the first-line setting. PROpel, he reiterated, is a global, phase III randomized controlled trial of olaparib in combination with abiraterone or abiraterone alone as first-line therapy in mCRPC. Importantly, included patients could have received docetaxel for metastatic castration sensitive disease but could not have received prior abiraterone. Other prior novel hormonal agents were allowed if they were stopped at least 12 months prior to enrollment. 

By blinded independent central review, PROpel showed a significant benefit in radiographic progression free survival to the combination approach. At the same time as PROpel, the MAGNITUDE trial was designed and conducted. While answering a similar question of the efficacy of combination therapy (this time with niraparib and enzalutamide), MAGNITUDE took a biomarker stratified approach with a built-in futility analysis in the biomarker negative (HRR negative) subset. 

This early futility analysis demonstrated no benefit to the combination approach in HRR negative patients and additional grade 3 and 4 toxicity. As such, this portion of the trial was closed. However, Dr. Clarke noted that only 83 PFS events and 65 rPFS had been observed at the time of closure.

In contrast, among the biomarker positive subset, there was a significant benefit in radiographic progression-free survival, whether assessed by central review or the investigator.

Dr. Clarke then considered why we may see these disparate results between PROpel and MAGNITUDE, highlighting that potential differences in patient populations, trial designs, pharmacology and pharmacokinetics between utilized agents, and the effect of prior abiraterone treatment may contribute. Assessing first the difference in patient populations, he highlighted that PROpel did not employ DDR selection, did not allow prior novel hormonal agents, utilized standard PARP inhibitor doses, had a lower proportion of BRCA mutated patients, and utilized a different novel hormonal agent (abiraterone). In contrast, the biomarker positive subset of MAGNITUDE included only patients with DDR mutations, enriched with a higher proportion of patients with BRCA mutations, prior use of abiraterone was allowed, and there was early termination of the non-DDR mutant subset.

Dr. Clarke noted that hormonal therapies can induce changes in androgen receptor signalling. Thus, the prior treatment allowed in MAGNITUDE may affect the efficacy of treatment administered on trial. Additionally, differing PARP inhibitors have different pharmacology and pharmacokinetics which may contribute to the differing results seen between these two trials. 

These differences in pharmacology and pharmacokinetics may have important clinical implications. Based on data presented as a poster at AACR 2018, each of five examined PARP inhibitors differs significantly regarding both cytotoxicity and tolerability. As a result of tolerability differences (and the combination with enzalutamide), the dose of niraparib in MAGNITUDE was decreased somewhat. Dr. Clarke further emphasized that there are differential effects of different PARP inhibitors in terms of PARP trapping. While all PARP inhibitors bind with relatively similar affinity, there may be differential PARP trapping due to differential PARP release.

Dr. Clarke then considered the futility analysis within MAGNITUDE in more detail. In his view, this was performed too early and, as a result, this arm was stopped too early (around 9 months of enrollment). He considered that, based on the available data, he argued that the “case [is] not proven” and we will need to wait overall survival data from PROpel.