PARP inhibitor extends PFS, OS in men with progressive mCRPC

May 4, 2020

“The outcomes and experience in the PROfound trial… represent major progress in the treatment of advanced prostate cancer that historically has not been considered amenable to genomic mutation-targeted therapy,” says Maha Hussain, MD.

The latest results from a phase 3 study investigating olaparib (Lynparza) as targeted treatment for metastatic castration-resistant prostate cancer (mCRPC) show that the PARP (poly [ADP-ribose] polymerase) inhibitor improved progression free and overall survival compared with abiraterone (Zytiga) or enzalutamide (Xtandi) in men with BRCA1/2 or ATM-mutated tumors that had progressed during treatment with one of those two standard of care hormonal agents.

Findings from the PROfound trial were published online ahead of print in the New England Journal of Medicine on April 28, 2020, and the overall survival results were announced in a press release from AstraZeneca, the company that markets olaparib. Details of the overall survival data, which was analyzed as a secondary endpoint in PROfound, will be presented at a future meeting.

As first reported in August 2019 at the European Society for Medical Oncology Congress in Barcelona, Spain, PROfound met its primary endpoint that looked at imaging-based progression-free survival (PFS) in men with mutations in BRCA1/2 or ATM. In addition, the international, randomized trial met a key secondary endpoint that considered PFS in the overall cohort that included patients with mutations in 12 other homologous recombination repair (HRR) genes.

A supplemental New Drug Application for olaparib to treat mCRPC in men with deleterious or suspected deleterious germline or somatic HRR gene mutations is currently under priority review at the FDA with a Prescription Drug User Fee Act date set for the second quarter of 2020.

PROfound investigator Maha Hussain, MD, described the benefit of olaparib for improving progression-free survival and overall survival as statistically significant and clinically meaningful and said she is hopeful regarding the FDA decision.

“Approval of olaparib as targeted therapy for mCRPC opens up the door for many things. Importantly, it provides an additional treatment option for men who are candidates for its use because they have the qualifying mutation,” said Hussain, of Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

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“I tell my patients that with every day they live longer and remain reasonably well, they gain opportunity for future treatments that may get approved or become available through a clinical trial.”

She added, “The outcomes and experience in the PROfound trial also represent major progress in the treatment of advanced prostate cancer that historically has not been considered amenable to genomic mutation-targeted therapy. We know from PROfound that it is possible to conduct a clinical trial in a genomically-preselected population, and the positive outcomes of the trial provide support for future research focusing on developing combination treatments that could deliver greater benefit and other targeted therapies that would make sense biologically for this disease.”

The PROfound trial enrolled patients who had a qualifying alteration in 1 or more of 15 prespecified genes having a direct or indirect role in HRR and stratified them into two cohorts based on their specific alteration(s). The primary cohort, which included 245 patients, was comprised of men with at least one alteration in BRCA1, BRCA2, or ATM. A total of 142 men with an alteration in any of the other 12 prespecified genes was included in the secondary cohort. Within each cohort, patients were randomized 2:1 to treatment with olaparib or the physician’s choice of enzalutamide or abiraterone.

Next: PFS significantly longer in olaparib group compared with controlsThe primary endpoint results showed that in men with BRCA1/2 or ATM mutations, PFS was significantly longer in the olaparib group compared with the controls (median 7.4 months vs 3.6 months). A significant benefit of the PARP inhibitor for improving PFS was also seen in analyses of the overall study population (median 5.8 vs 3.5 months) and in the secondary cohort.

Other secondary endpoints showed a statistically significant benefit of olaparib for improving the objective response rate and time to pain progression. Overall survival data were not yet mature at the data cutoff for the primary endpoint analysis, but an interim analysis for the primary cohort showed a trend favoring olaparib over control (18.5 vs 15.1 months).

Read: Genetic testing’s role centers on advanced prostate cancer

As data matured, AstraZeneca also announced on April 24 that the final overall survival analysis showed olaparib provided statistically and clinically meaningful overall survival benefit for mCRPC patients with BRCA1/2 or ATM mutation who failed prior enzalutamide or abiraterone treatment.

Safety data showed that olaparib was well-tolerated. Anemia (46%), nausea (41%), and fatigue or asthenia (41%) were the most common adverse events associated with its use. No new safety signals emerged using olaparib to treat men with mCRPC. The PARP inhibitor is currently available with indications for treating certain patients with ovarian, breast, or pancreatic cancer.

AstraZeneca and Merck Sharp & Dohme provided funding for the study. Hussain reports research support and honoraria with AstraZeneca and other companies that market or are developing drugs for the treatment of mCRPC.