APCCC 2022: Debate: PARP Inhibitors Only in Selected 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. de Bono presented the case for a selected, judicious use of PARP inhibitors in this setting.

Fundamentally, Dr. de Bono emphasized that, conceptually, we may be “lumpers” or “splitters”. However, we may adapt our approach to the specific hypothesis and question being examined. He emphasized that there is “incontrovertible” evidence that advanced prostate cancer is a highly heterogeneous condition. Conceptually, the concept of PARP inhibition is premised on synthetic lethality in which a tumor-restricted loss of both alleles (and resulting protein function) results in the vulnerability of the tumor to intervention which spares normal cells.

Based on clinical practice, and his prior experience as a primary investigator on phase I trials of each agent, he suggested that both olaparib and niraparib work similarly in patients with BRCA mutation. He noted, however, that the response to these agents is relatively limited to patients with homologous recombination repair (HRR) deficiency. Based on data from the TOPARP-A trial, almost all patients (save for one) who exhibited tumor response to single agent PARP inhibition (olaparib) were seen in patients with HRR mutation. 

Following TOPARP-A, the TOPARP-B trial showed that not only did BRCA patients benefit the most, super-responders had evidence of BRCA2 HOMDEL, a mutation profile that is somewhat difficult to detect.

Moving to data from the PROfound trial, he emphasized that Cohort A (BRCA1, BRCA2, and ATM) is the subset where the benefit has been seen. He then moved to discuss the two recent publications, PROpel and MAGNITUDE, assessing the role of combination therapy with PARP inhibition and abiraterone. He emphasized that MAGNITUDE utilized a biomarker driven selection approach prospectively, consistent with his “own bias”. This analysis included a pre-specified early futility analysis among the biomarker negative subset of patients. This showed no benefit to the combined approach, compared to abiraterone alone. Additionally, beyond the lack of efficacy, this treatment approach showed increased toxicity. However, the biomarker positive arm of this trial showed a benefit to the combined approach in patients with HRR deficits.

While all of this fit with a rationale explained by prior work, he moved to discuss PROpel, asking the question of whether there is a rationale for PARP inhibition to have activity in prostate cancers that do not have DDR alterations. If the rationale supporting a synergy between abiraterone and PARP inhibition is an induced “BRCA-ness”, he suggested that observed responses should rise to 80%. Instead, the PROpel data show an increase in objective response rate from 48.1 to 58.4%. While significant, this falls far short of what would be expected if patients were all biologically behaving as homologous recombination repair deficient.

Further, if PARP inhibition affected androgen receptor driven signaling, there should have been PSA responses seen in non-DDR patients. Alternatively, if AR blockade (through abiraterone) downregulates DNA repair pathways, we should expect much higher responses to PARP inhibition. He suggested that there may be some PARP mediated clearing of “escape clones” induced by androgen receptor signaling blockade, such as emerging neuroendocrine clones.

Dr. de Bono then drew parallels between the rPFS data from PROpel to prior work examining the use of platinum-based chemotherapy (another treatment approach with proven benefit in HRR deficient tumors) in advanced mCRPC. While this trial showed an rPFS benefit reminiscent of that seen in PROpel, there was no overall survival benefit seen. 

Currently, overall survival data from PROpel remain immature and these data will be important in understanding the role this combination approach will have moving forward. He further noted that, in subgroup analyses of PROpel examining HRR mutation status, that false negative results are “very likely” given the use of a plasma-based assay.

He further noted that our overall goal as clinicians should be to provide the maximal benefit while minimizing harm. PARP inhibitors are associated with not insignificant risks of leukemia and myelodysplatic syndrome. Thus, saving them for the patients at greatest likelihood of benefit was warranted in his perspective.