Sign Up Now!
To sign up for our newsletter or print publications, please enter your contact information below.
First Name *
Last Name *
Email Address (Verify) *
We will request your mailing address on the next page.
We will request your mailing address on the next page.

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

Web Exclusives - ESMO Highlights

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.

Related Items
Atezolizumab Extends Disease-Free Survival in PD-L1−Positive Early-Stage NSCLC
Phoebe Starr
Web Exclusives published on October 4, 2021 in Lung Cancer, ASCO Highlights
¹⁷⁷Lu-PSMA-617 Prolongs Survival in Patients with Metastatic Castration-Resistant Prostate Cancer
Phoebe Starr
Web Exclusives published on September 20, 2021 in Prostate Cancer, ASCO Highlights
Adjuvant Abemaciclib plus Endocrine Therapy Game-Changer in High-Risk, HR-Positive, HER2-Negative Early Breast Cancer
Phoebe Starr
Web Exclusives published on November 3, 2020 in ESMO Highlights
Trabectedin/PLD versus Carboplatin/PLD in Recurrent Ovarian Cancer Progressing within 6-12 Months After Last Platinum Line
Conference Correspondent  published on September 23, 2020 in ESMO Highlights
Safety and Efficacy of XMT-1536 in Ovarian Cancer: Subgroup Analysis from a Phase 1 Expansion Study
Conference Correspondent  published on September 23, 2020 in ESMO Highlights
Maintenance Olaparib plus Bevacizumab for Newly Diagnosed High-Grade Ovarian Cancer: Second Progression-Free Survival
Conference Correspondent  published on September 23, 2020 in ESMO Highlights
Real-World Data on Platinum Therapy in High-Grade Serous Ovarian Cancer Patients Progressing After PARP Inhibitor Treatment
Conference Correspondent  published on September 23, 2020 in ESMO Highlights
Atezolizumab in Patients with Newly Diagnosed Stage III or Stage IV Ovarian Cancer
Conference Correspondent  published on September 23, 2020 in ESMO Highlights
Mirvetuximab Soravtansine in Combination with Carboplatin and Bevacizumab in Recurrent Ovarian Cancer
Conference Correspondent  published on September 22, 2020 in ESMO Highlights
Patient-Reported Outcomes in Patients Receiving Niraparib in the PRIMA/ENGOT-OV26/GOG-3012 Trial
Conference Correspondent  published on September 22, 2020 in ESMO Highlights
Copyright © Green Hill Healthcare Communications, LLC. All rights reserved.