medwireNews: Adding olaparib to durvalumab did not improve progression-free survival (PFS) in the overall BAYOU trial population comprising unselected patients with metastatic urothelial carcinoma (UC), but there was a signal of efficacy in the subgroup with homologous recombination repair (HRR) gene mutations, say investigators.
The findings were presented by Jonathan Rosenberg, from Memorial Sloan Kettering Cancer Center in New York, USA, at the 2022 ASCO Genitourinary Cancers Symposium in San Francisco, California, USA.
The double-blind, phase 2 BAYOU study was instigated to investigate whether PARP inhibition enhances the antitumor response of immune checkpoint blockade.
For the study, 154 platinum-ineligible individuals who had not received prior systemic therapy for unresectable stage IV UC were randomly assigned to receive durvalumab 1500 mg every 4 weeks alongside either olaparib 300 mg twice a day or matching placebo.
Over a median follow-up of 9.8 months in the olaparib group and 10.7 months in the placebo group, the primary endpoint of investigator-assessed PFS in the intention-to-treat population did not differ significantly between the groups, at a median of 4.2 and 3.5 months, respectively.
Median overall survival (OS) was likewise comparable between the olaparib and placebo study arms, at 10.2 versus 10.7 months.
However, in a prespecified secondary analysis focusing on the 20% of patients harboring HRR gene mutations, median PFS was 5.6 months for olaparib-treated patients and 1.8 months for those given placebo, a significant difference equating to a hazard ratio for progression or death of 0.18 in favor of the PARP inhibitor.
Combined treatment with durvalumab plus olaparib was also associated with a numerically longer median OS in this subgroup, at 8.6 months versus 5.8 months for durvalumab plus placebo, and a nonsignificant hazard ratio of 0.56.
But Rosenberg pointed out that OS seemed to be poorer among patients with versus without HRR mutations regardless of whether they received olaparib (median, 8.6 vs 10.9 months) or placebo (5.8 vs 13.7 months), suggesting that these patients with HRR-mutated tumors “might be a poor prognosis group.”
He cautioned, however, that all of these results should be taken as hypothesis generating.
In terms of the adverse event (AE) profile, the presenter noted that “no new safety signals were observed with the combination of durvalumab and olaparib.”
In the overall trial population, treatment-related adverse events of grade 3–4 occurred in 18.4% of the participants treated with olaparib and 9.2% of those who received placebo, with anemia the most common event of this severity in the olaparib group (6.6 vs 1.3%). One death in the placebo group was considered related to study treatment by the investigator.
Rosenberg concluded that the PFS results in the HRR-mutant patient group suggest a potential role for PARP inhibitors in the treatment of metastatic UC with HRR mutations, and he believes “further investigation is warranted.”
Sandy Srinivas (Stanford University, California, USA), who discussed the presentation, said that “the combination of durvalumab and olaparib does have activity in HRR-mutant patients compared to durvalumab [alone], but it’s really unclear if this would be superior to PARP inhibitor monotherapy” in these patients.
“And we await the olaparib monotherapy trial in [a] biomarker-selected population,” she concluded.
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This independent news story was supported by an educational grant from Pfizer and Merck Healthcare KGaA, Darmstadt, Germany