No benefit of olaparib in previously untreated, platinum-ineligible, metastatic urothelial carcinoma

In the phase 2 BAYOU trial, first-line treatment with durvalumab plus olaparib did not prolong survival of patients with platinum-ineligible, unresectable, stage IV urothelial carcinoma compared with durvalumab plus placebo.

The prognosis for patients with advanced urothelial carcinoma remains poor, particularly for those unable to tolerate platinum-based chemotherapy [1]. Mutations in homologous recombination repair (HRR) genes are common in urothelial carcinoma and render tumour cells sensitive to PARP inhibition [2]. PARP inhibition may enhance the anti-tumour response of immune checkpoint inhibitors.

The randomised, phase 2 BAYOU study (NCT03459846) intended to evaluate durvalumab in combination with olaparib or placebo as a first-line treatment for platinum-ineligible patients with unresectable, stage IV urothelial carcinoma. BAYOU enrolled 154 patients (age ≥18 years, ECOG performance status 0, 1, or 2, histologically or cytologically confirmed transitional cell carcinoma) who had not received prior systemic therapy. Participants were randomised 1:1 to receive durvalumab plus olaparib or durvalumab plus placebo. Patients were stratified according to centrally-determined HRR status (mutant vs wildtype) and Bajorin risk index. The primary endpoint was progression-free survival (PFS) in the intention-to-treat (ITT) population. Secondary endpoints included overall survival (OS) in the ITT population and PFS in the subset of patients with HRR mutations. Dr Jonathan Rosenberg (Memorial Sloan Kettering Cancer Center, NY, USA) presented the results of BAYOU [3].

Among all randomised patients at baseline, 20% had an HRR mutation. Median PFS in the ITT population was not significantly different between both treatment arms (4.2 vs 3.5 months in the durvalumab plus olaparib and durvalumab plus placebo arm, respectively; HR 0.94; P=0.789). In the subset of patients with HRR mutations (n=31), median PFS was 5.6 versus 1.8 months, respectively (HR 0.18; P<0.001). In the ITT population, median OS was 10.2 months in the durvalumab plus olaparib arm versus 10.7 months in the durvalumab plus placebo arm (HR 1.07; P=0.728). Median OS in the HRR-mutated patients was 8.6 versus 5.8 months, respectively (HR 0.56).

Among all treated patients, grade 3 or 4 treatment-related adverse events occurred in 18% and 9% in the durvalumab plus olaparib and durvalumab plus placebo arms.

“The BAYOU study did not meet its primary endpoint,” concluded Dr Rosenberg. “However, the results of pre-planned secondary analyses suggest a potential role for PARP inhibition in urothelial carcinoma patients harbouring HRR-mutated disease. Further investigation is warranted.”

1. Pond GR, et al. Clin Genitourin Cancer. 2021;19:425–433.
2. Rimar KJ, et al. Cancer. 2017;123:1912–1924.
3. Rosenberg JE, et al. BAYOU: A phase II, randomized, multicenter, double-blind, study of durvalumab (D) in combination with olaparib (O) for the first-line treatment of platinum-ineligible patients with unresectable, stage IV urothelial carcinoma (UC). Abstract 437, ASCO GU 2022, 17–19 February.

 

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Posted on 8 April 202217 May 2024