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Efficacy Outcomes of Olaparib in Patients with mCRPC with BRCA Alterations Whose Disease Had Progressed on Next-Generation Hormonal Agent

Findings from an exploratory post hoc analysis of the subgroup of patients with BRCA alterations in PROfound study
21 Nov 2023
Targeted Therapy;  Molecular Oncology;  Endocrine Therapy
Prostate Cancer

In a post hoc exploratory analysis of patients with a BRCA alteration included in PROfound study, treatment with olaparib compared with abiraterone or enzalutamide led to radiographic progression-free survival (rPFS) and overall survival (OS) benefit for patients with metastatic castration-resistant prostate cancer (mCRPC) and a BRCA alteration whose disease had progressed on prior treatment with next-generation hormonal agent (NHA). Confirmed overall response rate (ORR), PSA, and circulating tumour cell (CTC) results were consistent with the rPFS and OS findings.

The treatment benefit with olaparib was observed in all subgroups assessed, including subgroups based on previous taxane exposure, crossover to olaparib treatment, germline/somatic origin of the BRCA alteration, and zygosity by targeted next generation sequencing. The findings are published by Dr. Joaquin Mateo of the Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital in Barcelona, Spain, and colleagues on 14 November 2023 in the JCO.

The authors explained in background that approximately 20-25% of patients with mCRPC have alterations in genes associated with homologous recombination repair (HRR), approximately 1% BRCA1 and 7-13% BRCA2. PROfound was a phase III randomised, open-label study of olaparib versus physicians' choice of abiraterone or enzalutamide for patients with mCRPC with a deleterious or suspected deleterious alteration in ≥1 of 15 genes with a direct or indirect role in HRR who had experienced disease progression on a previous NHA.

Phase III PROfound study met its primary and key secondary objectives, demonstrating significantly longer rPFS and OS with olaparib monotherapy versus abiraterone or enzalutamide (control) in patients with mCRPC with alterations in BRCA1, BRCA2, and/or ATM (cohort A) whose disease had progressed on prior NHA.

Patients with alterations in BRCA and/or ATM genes (cohort A) treated with olaparib versus abiraterone, or enzalutamide had significantly longer rPFS with median 7.4 versus 3.6 months (hazard ratio [HR] 0.34, 95% confidence interval [CI] 0.25 to 0.47]; p < 0.001) and OS with median 19.1 versus 14.7 months (HR 0.69, 95% CI 0.50 to 0.97; p = 0.02). A statistically significant rPFS benefit with olaparib was observed in the overall study population with median 5.8 versus 3.5 months (HR 0.49, 95% CI 0.38 to 0.63; p < 0.001). The HR for OS in the overall study population was 0.79 (95% CI 0.61 to 1.03).

For PROfound, some rPFS and OS data, including those by previous taxane, have been previously reported. In the latest article published in the JCO, the study team presents consolidated exploratory analyses on safety and efficacy outcomes specifically for patients with BRCA alterations, pursuing further analyses by germline versus somatic (tumour-only) origin and zygosity status of the BRCA alterations.

All patients had an alteration in HRR gene by tumour tissue testing, of which 160 had underlying BRCA alterations. Olaparib was associated with longer rPFS (HR 0.22, 95% CI 0.15 to 0.32) and OS (HR 0.63, 95% CI 0.42 to 0.95) than control. There was an rPFS benefit with olaparib in all zygosity subgroups (biallelic [n = 88]; HR 0.08, 95% CI 0.04 to 0.16, heterozygous [n = 15] and unknown [n = 57]; HR 0.30, 95% CI 0.16 to 0.60). Patients with BRCA2 homozygous deletions experienced prolonged responses to olaparib (n = 16; median rPFS 16.6 months, 95% CI 9.3 to not reached).

The authors commented that some evaluations are limited by small patient numbers. Germline DNA analysis was performed for 112 (70%) patients; risk of disease progression was similar for patients with germline (n = 61; HR 0.08, 95% CI 0.03 to 0.18) and somatic (n = 51; HR 0.16, 95% CI 0.07 to 0.37) BRCA alterations.

These findings are important as approximately 10% of patients with mCRPC have alterations in BRCA1 and BRCA2 genes, which are associated with more aggressive disease and poorer outcomes.

A higher proportion of patients in the olaparib arm than in the control arm had reductions from baseline in target lesions, PSA levels, and CTC levels. In patients who were evaluable by RECIST v1.1, confirmed ORR was 43.9% and 0% in the olaparib and control arms. Confirmed PSA response was 61.7% and 0% in the olaparib and control arms. CTC conversion was 69.0% for olaparib-treated patients and 23.5% for patients receiving control.

The findings were presented previously in part at the 2021 ASCO Genitourinary Cancers Symposium.

The study was supported by AstraZeneca and is part of an alliance between AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ.


Mateo J, de Bono JS, Fizazi K, et al. Olaparib for the Treatment of Patients With Metastatic Castration-Resistant Prostate Cancer and Alterations in BRCA1and/or BRCA2 in the PROfound Trial. JCO; Published online 14 November 2023. DOI: 10.1200/JCO.23.00339

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