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Targeted Therapy with Olaparib Beneficial in Metastatic Prostate Cancer with Gene Mutations

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Barcelona, Spain—The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib (Lynparza) delayed disease progression and showed a trend toward improved survival compared with newer hormonal agents in men with pretreated metastatic castrate-resistant prostate cancer (CRPC) and homologous recombinant repair (HRR) gene mutations or with BRCA1, BRCA2, and ATM mutations. Results of this late-breaker were reported at the ESMO Congress 2019 during the presidential session.

The PROfound study is the first phase 3, biomarker-driven clinical trial to show a benefit for a targeted therapy in metastatic CRPC. The results underscore the need for genetic testing to select patients with prostate cancer who can benefit from a targeted therapy. Olaparib is currently approved for BRCA-positive breast cancer or ovarian cancer.

In this study, olaparib delayed disease progression by approximately 4 months compared with newer hormonal agents, and survival was prolonged by >3 months at this early time point. All secondary end points favored olaparib over hormone therapy, including objective response rate, time to disease progression, and overall survival.

“In metastatic CRPC that has progressed on front-line hormonal therapy with abiraterone or enzalutamide, olaparib provides statistically significant and clinically meaningful progression-free survival in patients with metastatic CRPC and BRCA1, BRCA2, or ATM genetic alterations,” said lead investigator Maha H.A. Hussain, MD, FACP, FASCO, Deputy Director, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL.

“PROfound is the first positive biomarker-selected phase 3 study evaluating a molecularly targeted therapy in men with metastatic CRPC and the largest to have central HRR mutation testing,” Dr Hussain emphasized. “This study highlights the importance of genomic testing in this population. A recurring theme is that precision medicine trials are feasible in metastatic CRPC.”

Study Results

The study enrolled 387 men with metastatic CRPC who were preselected for HRR genetic alterations and randomized to treatment with olaparib 300 mg twice daily or to physician’s choice of enzalutamide (Xtandi) or abiraterone acetate (Zytiga) plus prednisone. Enrollment criteria specified alterations of any of 15 predetermined HRR genes with a direct or indirect role with progressive disease.

Cohort A included 245 patients (median age, 68 years) with alterations in BRCA1, BRCA2, or ATM; cohort B included 142 men with 1 of 12 other HRR alterations (ie, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RA51D, or RAD54L). Crossover to olap­arib was allowed at disease progression.

The patient population was relatively heavily pretreated. All had disease that progressed with ≥1 lines of androgen-deprivation therapies.

For the primary end point for cohort A, median radiographic progression-free survival (PFS) was 7.39 months versus 3.5 months in the comparator arm, a 66% reduction in disease progression (P <.0001).

For all patients enrolled in the trial, median PFS was 5.82 months with olaparib versus 3.52 months in the comparator arm, for a 51% reduction in risk of disease progression (P <.0001).

Olaparib was generally well-tolerated. Higher rates of adverse events were reported with olaparib, but they were mainly mild; grade ≥3 anemia was 21%. More treatment discontinuations because of adverse events were reported with olaparib: 16.4% compared with 8.5% in the comparator arm.

Ongoing studies are exploring PARP inhibitors as first-line therapy in prostate cancer alone or in combination with newer hormonal agents.

Expert’s Comments

“This is truly a practice-changing study, not just for our patients but for the design of other studies. We can successfully identify candidates for olaparib. We saw a clinically meaningful improvement in outcomes for patients with HRR genetic alterations, driven mainly by BRCA2,” said Eleni Efstathiou, MD, PhD, Associate Professor, Department of Genitourinary Medical Oncology, M.D. Anderson Cancer Center, Houston, TX, commenting on the findings.

“We are entering the targeted therapy era for prostate cancer….We need to treat earlier in the disease and decide which genes to target,” Dr Efstathiou commented.

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