Olaparib was found to prolong survival in patients with BRCA1/2-mutant metastatic castration-resistant prostate cancer (mCRPC), but had limited antitumor activity against disease harboring mutations in other homologous recombination repair (HRR) genes, according to the results of a gene-by-gene analysis of the PROfound trial population presented at the 2021 Genitourinary Cancers Symposium.

In the phase 3 PROfound trial (NCT02987543), olaparib was found to confer an overall survival (OS) benefit in men with mCRPC who harbored BRCA1/2 or ATM mutations. The PROfound study enrolled 387 men with mCRPC with a qualifying HRR gene mutation who experienced disease progression on prior therapy with a new hormonal agent. The men were randomly assigned to receive olaparib monotherapy or physician’s choice of either enzalutamide or abiraterone acetate.

In this gene-by-gene exploratory analysis, De Bono et al studied olaparib’s antitumor activity against 15 prespecified mutated HRR genes. The most common gene alterations were seen in BRCA2, ATM, and CDK12. Eighty-four patients, 39 patients, and 43 patients had a BRCA1 and/or BRCA2, ATM, or CDK12 alteration, respectively.

Olaparib benefit was greatest among those with BRCA alterations. Findings showed that olaparib significantly improved the objective response rate (ORR) and survival in this subset. Specifically, the ORR was 43.9% with olaparib compared with 0% with enzalutamide or abiraterone.


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The median radiographic progression-free survival (rPFS) was 9.8 months with olaparib vs 3.0 months with enzalutamide or abiraterone (HR, 0.22; 95% CI, 0.15-0.32). The median OS was 20.1 and 14.4 months with olaparib vs enzalutamide or abiraterone, respectively (HR, 0.63; 95% CI, 0.42-0.95).

Olaparib monotherapy also resulted in a higher ORR vs enzalutamide or abiraterone in patients whose disease harbored alterations in CDK12 (5.9% vs 0%) but not ATM (10.0% vs 10.0%). There was no significant difference in rPFS or OS among patients with ATM or CDK12 alterations. However, the study authors noted that “small subgroups limit interpretation for some genes.”

The findings from the gene-by-gene exploratory analysis “support the importance of genomic testing to identify patients eligible to consider olaparib treatment,” concluded Johann S. De Bono, FRCP, MB, MD, PhD, who presented the data.

Disclosures: Some of the study authors disclosed financial relationships with the pharmaceutical industry and/or the medical device industry. For a full list of disclosures, please refer to the original study. This research was supported by AstraZeneca and Merck Sharp & Dohme Corp.

Reference

De Bono JS, Matsubara N, Penel N, et al. Exploratory gene-by-gene analysis of olaparib in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): PROfound. Presented at: 2021 Genitourinary Cancers Symposium; February 11-13, 2021. Abstract 126.

This article originally appeared on Cancer Therapy Advisor

Source: Renal & Urology News

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