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Reserve PARP Inhibitors for mCRPC With BRCA Mutations

For men with metastatic castration-resistant prostate cancer (mCRPC), any new therapy that offers the chance of a higher response rate or longer survival compared with the standard of the care would be welcome.

The US Food and Drug Administration (FDA) recently approved two such drugs for use in men with mCRPC: the poly (ADP-ribose) polymerase (PARP) inhibitors rucaparib (Rubraca) and olaparib (LynParza).

Both drugs were approved for use in the treatment of men with advanced prostate cancer with deleterious germline and/or somatic BRCA mutations following treatment with androgen receptor–directed therapy and taxane-based chemotherapy.

But there was difference in the wording of the indication that was approved, as noted by Michael T. Schweizer, MD, and colleagues from the Fred Hutchinson Cancer Research Center and the University of Washington in Seattle, Washington, in a recent commentary published in the Journal of Clinical Oncology.

Olaparib received wider approval for treatment of “deleterious or suspected deleterious germline or somatic homologous recombination repair gene (HRR)–mutated metastatic castration-resistant prostate cancer” with disease progression following therapy with either enzalutamide or abiraterone (Zytiga).

It’s the “deleterious or suspected deleterious” part of that indication that has these experts concerned, inasmuch as this may lead to the drug being used injudiciously to treat some patients who might better be treated with other approaches.

“Using standard-of-care PARP inhibitors in those with uncertain or little chance of benefit could mean missing a window of opportunity for more effective therapy. This may result in decreased survival and hamper clinical trial enrollment to the very studies that could define the predictive utility of individual genes,” they write.

Elaborating in an interview with Medscape Medical News, Schweizer said: “The issue is that olaparib has a long list of genes that would make you eligible to receive it, but it’s not clear that many of these genes are good biomarkers for response to that drug.”

Although the evidence for a response to PARP inhibitors for patients with BRCA mutations is fairly strong, there has not been sufficient evidence to date to suggest that responses would be adequate for patients with other HRR mutations, he said.

For patients who have “one of the less common HRR genes, maybe without high level of evidence that they are really predictive of response, I would still give careful consideration to some of the other drugs that have been around for a while and that we know have a track record of working well for prostate cancer, such as taxane-based chemotherapy,” Schweizer commented.

Mark Pomerantz, MD, a geneticist and specialist in genitourinary oncology at the Dana-Farber Cancer Institute in Boston, Massachusetts, who was not involved in the study, told Medscape Medical News that Schweizer and colleagues are “exactly right.”

“The landmark studies leading to the approval of the two PARP inhibitors for prostate cancer were critical studies,” Pomerantz said in an interview. “What they do not address, however, is the full expanse or limitation of patients who benefit the most from these drugs.”

The editorial is “a call