Olaparib Benefit for Patients With Metastatic Castration-Resistant Prostate and BRCA Alterations Consistent Across Subgroups

Subgroup Analysis of Phase 3 PROfound Trial

Olaparib improved radiographic progression-free survival (rPFS) and overall survival (OS) across all subgroups when compared with abiraterone or enzalutamide among patients with metastatic castration-resistant prostate cancer with BRCA alterations whose disease had progressed on a previous next-generation hormonal agent.

Joaquin Mateo, MD, Vall d’Hebron Institute of Oncology, Barcelona, Spain, and coauthors wrote, “Approximately 20% to 25% of patients with [metastatic castration-resistant prostate cancer] have alterations in genes associated with homologous recombination repair (HRR) and HRR gene alterations, particularly BRCA1 and BRCA2 are associated with a more aggressive prostate cancer phenotype, as well as increased tumor sensitivity to PARP inhibitors.”

PROfound was a randomized, open-label phase 3 trial evaluating olaparib vs physician’s choice of either abiraterone or enzalutamide among patients with metastatic castration-resistant prostate cancer with a deleterious or suspected deleterious alteration in ≥1 of the 15 genes with a direct or indirect role in HRR, who had experienced disease progression on a previous next-generation hormonal agent. It has previously been reported that PROfound met its primary and secondary end points, with longer rPFS and OS with olaparib monotherapy vs abiraterone or enzalutamide. This exploratory post hot analysis looked at the efficacy and safety outcomes specifically in the subgroup of patients with BRCA alterations within the PROfound trial. This analysis included information by germline vs somatic origin and zygosity status of BRCA alterations.

The rPFS benefit from olaparib was seen across all zygosity subgroups; the hazard ratio (HR) of the biallelic subgroup (n = 88) was 0.08 and the HR for the heterozygous (n = 15) and unknown (n = 57) subgroup was 0.30. There was a prolonged response to olaparib among patients with BRCA2 homozygous deletions (n = 16) with a median rPFS of 16.6 months. Germline DNA analyses were performed on 112 patients and risk of disease progression was similar for patients with germline and somatic BRCA alterations (HR, 0.08 vs HR, 0.16).

This analysis “shows consistent clinical benefits with olaparib versus abiraterone or enzalutamide. These benefits were observed for all BRCA subgroups within the population of PROfound,” stated Dr Mateo et al.

Associate editor for Journal of Clinical Oncology, Michael A. Carducci, MD, Johns Hopkins Medicine, Baltimore, Maryland, added, “Individuals with BRCA2 alterations, either of germline or somatic origin, appear to have prolonged or exceptional responses reinforcing recommendations for poly(ADP-ribose) polymerase inhibition in these men.”

Source:

Mateo J, de Bono JS, Fizazi K, et al. Olaparib for the treatment of patients with metastatic castration-resistant prostate cancer and alterations BRCA1 and/or BRCA2 in the PROfound trial. J Clin Oncol. Published online November 14, 2023. doi:10.1200/JCO.23.00339