Niraparib regimen fails to improve PFS among subset of patients with urothelial carcinoma
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SAN FRANCISCO — The addition of niraparib to best supportive care failed to extend PFS among patients with advanced urothelial carcinoma who did not experience progression after first-line platinum-based chemotherapy, study results showed.
Niraparib (Zejula, GlaxoSmithKline), an oral inhibitor of poly ADP-ribose polymerase (PARP) enzyme, had a safety profile consistent with that reported in studies of other solid tumors, according to the findings, presented at ASCO Genitourinary Cancers Symposium.
Homologous recombination deficiency (HRD), found in 10% to 25% of bladder cancers, sensitizes cancer cells to PARP inhibitors, according to Francesca Vignani, MD, of the department of medical oncology at Ordine Mauriziano Hospital in Turin, Italy.
“We also know that HRD is associated with platinum sensitivity in multiple tumor types, including urothelial tumors,” she said during a presentation. “There is potential cross-sensitivity and cross-resistance between platinum drugs and PARP inhibitors.”
In the randomized phase 2 Meet-URO12 trial, Vignani and colleagues compared the combination of niraparib and best supportive care with best supportive care alone as maintenance therapy among 58 patients (median age, 69.6 years; 74.1% men) with unresectable, locally advanced or metastatic transitional cell carcinoma of the urothelium. All patients had an ECOG performance score of 0 (65.5%) or 1 (34.5%), and received first-line treatment with cisplatin (51.7%) or carboplatin (48.3%) that conferred a partial response (50%), stable disease (44.8%) or complete response (5.2%).
Researchers randomly assigned patients 2:1 to niraparib dosed at 300 mg or 200 mg daily based on body weight and baseline platelets plus best supportive care (n = 39) or best supportive care alone (n = 19).
PFS served as the primary endpoint, with a primary hypothesis of 7-month PFS in the niraparib group and 4-month PFS in the control group. The study needed 65 PFS events to detect a hazard ratio of 0.57 with 80% power and one-tailed alpha of 0.1.
Investigators stopped accrual prematurely because of the availability of avelumab (Bavencio; EMD Serono, Pfizer) in the same setting, and they amended protocol to conduct the analysis with at least 40 PFS events.
After median follow-up of 8.5 months, 33 PFS events occurred in the niraparib group vs. 14 events in the control group. Vignani reported median PFS of 2.1 months with the niraparib regimen and 2.4 months with best supportive care alone (adjusted HR = 0.87; 95% CI, 0.46-1.67).
Results also showed no significant difference in median PFS between the groups among 47 patients with known pathogenic mutations (2 months vs. 1.9 months) and 21 patients with mutations in any homologous recombination repair genes (2 months for both groups).
Grade 3 or higher treatment-emergent adverse events occurred among 65.8% of patients in the niraparib group and 15.8% of patients with best supportive care alone. The most common adverse events with niraparib included anemia (50% overall, 10.5% grade 3), thrombocytopenia (36.8% overall, 15.8% grade 3 to grade 4), neutropenia (21.1% overall, 5.3% grade 3), fatigue (31.6% overall, 15.8% grade 3) and constipation (31.6% overall, 2.6% grade 3).
Nearly half of patients in the niraparib group (47.4%) required a dose reduction of the agent.
“Clinical selection based on platinum sensitivity did not succeed in selecting patients who may benefit from niraparib,” Vignani said. “As for molecular selection, analysis of the predictive role of HRD status for niraparib efficacy is limited by the small number of patients. Future studies could evaluate potential synergy of PARP inhibitors in combination with other therapies such as immune checkpoint inhibitors.”
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Vignani F, et al. Abstract 442. Presented at: ASCO Genitourinary Cancers Symposium; Feb. 17-19, 2022; San Francisco.
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