As reported in the Journal of Clinical Oncology by Jonathan E. Rosenberg, MD, and colleagues, the phase II BAYOU trial has shown no improvement in progression-free survival with the addition of the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib to the anti–PD-L1 agent durvalumab in previously untreated, platinum-ineligible patients with metastatic urothelial carcinoma. Benefit was observed in a subgroup of patients with homologous recombination repair (HRR) gene mutations, mutations that are common in urothelial carcinoma and render tumor cells sensitive to PARP inhibition.
Jonathan E. Rosenberg, MD
In the double-blind, multinational trial, 154 patients were randomly assigned between March 2018 and September 2019 to receive durvalumab at 1,500 mg once every 4 weeks plus olaparib at 300 mg twice daily (n = 78) or placebo (n = 76). Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed progression-free survival. A total of 17 patients (21.8%) in the durvalumab/olaparib group and 14 (18.4%) in the control group had HRR mutations.
At data cutoff (in October 2020), the median duration of follow-up was 9.8 months (range = 0.0–29.0 months) in the durvalumab/olaparib group and 10.7 months (range = 1.0–29.0 months) in the control group. Median progression-free survival was 4.2 months (95% confidence interval [CI] = 3.6–5.6 months) in the durvalumab/olaparib group vs 3.5 months (95% CI = 1.9–5.1 months) in the control group (hazard ratio [HR] = 0.94, 95% CI = 0.64–1.39, P = .789). Among patients with HRR mutations, median progression-free survival was 5.6 months (95% CI = 1.9–8.1 months) in the durvalumab/olaparib group vs 1.8 months (95% CI = 1.7–2.2 months) in the control group (HR = 0.18, 95% CI = 0.06–0.47).
Subsequent anticancer therapy was received by approximately 20% of patients in each group. Median overall survival was 10.2 months (95% CI = 7.0–13.9 months) in the durvalumab/olaparib group vs 10.7 months (95% CI = 7.2–17.3 months) in the control group (HR = 1.07, 95% CI = 0.72–1.61). Among patients with HRR mutations, median overall survival was 8.6 months vs 5.8 months (HR = 0.56, 95% CI = 0.25–1.23).
Treatment-related grade 3 or 4 adverse events occurred in 18.4% of patients in the durvalumab/olaparib group vs 9.2% of the control group, with the most common in the durvalumab/olaparib group being anemia (6.6%) and neutropenia (2.2%). Treatment-related serious adverse events occurred in 14.5% vs 11.8% of patients. Adverse events led to death in 7.9% vs 6.6% of patients; one death in the control group, due to anemia, was considered possibly related to treatment.
The investigators concluded, “Adding olaparib to durvalumab did not improve survival outcomes in an unselected metastatic urothelial carcinoma population. Efficacy outcomes with durvalumab were similar to those reported for other anti–PD-1/PD-L1 agents. However, the results of secondary analyses suggest a potential role for PARP inhibition in patients with urothelial carcinoma harboring HRR mutations.”
Dr. Rosenberg, of the Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by a grant from the National Cancer Institute and by AstraZeneca. For full disclosures of the study authors, visit ascopubs.org.
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