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PROfound Trial: Olaparib for Patients With Metastatic Castration-Resistant Prostate Cancer and Homologous Recombination Repair Gene Alterations


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In a phase III trial reported in The New England Journal of Medicine, Johann de Bono, MB, ChB, PhD, and colleagues found that olaparib significantly improved progression-free survival vs hormonal therapy in patients with metastatic castration-resistant prostate cancer who had alterations in the BRCA1, BRCA2, or ATM genes, as well as among a combined population of patients with these alterations and those with alterations in other genes involved in homologous recombination repair.

Johann de Bono, MB, ChB, PhD

Johann de Bono, MB, ChB, PhD

As stated by the investigators, “Multiple loss-of-function alterations in genes that are involved in DNA repair, including homologous recombination repair, are associated with response to…PARP inhibition in patients with prostate and other cancers.”

Study Details

The trial included men whose disease had progressed while receiving treatment with enzalutamide or abiraterone. Patients were randomly assigned 2:1 within two cohorts between April 2017 and November 2018 to receive either olaparib at 300 mg twice daily, or physician’s choice of enzalutamide at 160 mg once daily or abiraterone at 1,000 mg once daily plus prednisone at 5 mg twice daily (control group). Cohort A comprised 162 patients in the olaparib group and 83 in the control group with at least one alteration in the BRCA1, BRCA2, or ATM genes. Cohort B comprised 94 patients in the olaparib group and 48 in the control group with alterations in any of 12 other prespecified genes involved in homologous recombination repair. The primary endpoint was imaging-based progression-free survival in cohort A on blinded independent central review. Major secondary endpoints included progression-free survival in the combined cohorts.

Progression-Free Survival

In cohort A, median progression-free survival was 7.4 months in the olaparib group vs 3.6 months in the control group (hazard ratio [HR] = 0.34, P < .001). Objective response rates among evaluable patients were 33% vs 2% (odds ratio [OR] = 20.86, P < .001). Median time to pain progression was significantly prolonged in the olaparib group (HR = 0.44, P = .02; 84% vs 67% progression-free at 6 months). Overall, 81% of patients with disease progression in the control group crossed over to receive olaparib. An interim analysis showed median overall survival of 18.5 months vs 15.1 months (HR = 0.64, P = .02).

KEY POINTS

  • Olaparib significantly improved progression-free survival in patients with BRCA1, BRCA2, or ATM genetic alterations.
  • Benefit was observed in the total population of patients with alterations in genes involved in homologous recombination repair.

In the combined populations of cohort A and cohort B, median progression-free survival was 5.8 months in the olaparib group vs 3.5 months in the control group (HR = 0.49, P < .001). Objective response rates among evaluable patients were 22% vs 4% (OR = 5.93, 95% confidence interval = 2.01–25.40). At 6 months, 85% vs 75% of patients were free of pain progression. A total of 82% of control group patients crossed over to olaparib at independent review–confirmed imaging-based disease progression. Interim analysis showed median overall survival of 17.5 months vs 14.3 months (HR = 0.67, 95% CI = 0.49–0.93).

Adverse Events

Among all patients, grade ≥ 3 adverse events occurred in 51% of patients in the olaparib group vs 38% of the control group, with the most common in the olaparib group being anemia (21%). The most common adverse events of any grade were anemia, nausea, and fatigue/asthenia in the olaparib group and fatigue/asthenia in the control group. Pulmonary embolism occurred in 11 patients (4%) in the olaparib group and in 1 patient in the control group; no fatal cases were reported. No cases of myelodysplastic syndromes or acute myeloid leukemia were observed.

The investigators concluded, “In men with metastatic castration-resistant prostate cancer who had disease progression while receiving enzalutamide or abiraterone and who had alterations in genes with a role in homologous recombination repair, olaparib was associated with longer progression-free survival and better measures of response and patient-reported endpoints than either enzalutamide or abiraterone.”

Disclosure: The study was funded by AstraZeneca and Merck Sharp & Dohme. For full disclosures of the study authors, visit nejm.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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