Efficacy of PARP Inhibition in Metastatic Castration-resistant Prostate Cancer is Very Different with Non-BRCA DNA Repair Alterations: Reconstructing Prespecified Endpoints for Cohort B from the Phase 3 PROfound Trial of Olaparib

The PROfound trial evaluated the PARP inhibitor olaparib in metastatic castration-resistant prostate cancers harboring alterations in BRCA1/2 and ATM (cohort A) and in 12 other homologous recombination repair genes (cohort B). Olaparib led to more objective responses and longer radiographic progression-free survival than the control in cohort A and when cohorts A and B were combined. The efficacy of olaparib in cohort B was a secondary objective prespecified in the trial protocol but was not reported. Reconstructing patient-level data for cohort B, two of 54 patients (4%) in the olaparib arm and two of 24 patients (8%) in the control arm had a radiographic response, and there was no evidence that olaparib prolonged radiographic progression-free survival in cohort B (hazard ratio 0.88, 95% confidence interval 0.58-1.34). These results are in strong contrast to cohort A. Patient summary: A large clinical study concluded that treatment with the PARP inhibitor olaparib benefits men with metastatic castration-resistant prostate cancer whose tumors harbor alterations in 15 different DNA repair genes. In contrast to the group dominated by BRCA alterations, any potential benefit from olaparib was considerably less, if present at all, for men with prostate cancers harboring one of the 12 other, non-BRCA DNA repair alterations. (C) 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Automated summary

The PROfound trial found that treatment with the PARP inhibitor olaparib benefits men with metastatic castration-resistant prostate cancer harboring alterations in 15 different DNA repair genes. However, the benefit of olaparib was less significant, if present at all, for men with prostate cancer harboring non-BRCA DNA repair alterations compared to those with BRCA alterations.