Berzosertib addition fails to extend metastatic UC survival
medwireNews: Progression-free survival (PFS) for patients with metastatic urothelial carcinoma (UC) is not extended by the addition of berzosertib to cisplatin–gemcitabine chemotherapy, indicates research presented at the 2021 ASCO Annual Meeting.
Sumanta Pal (City of Hope Comprehensive Cancer Center, Duarte, California, USA) reported the results for the phase 2 trial of the first-in-class ataxia telangiectasia and Rad3-related (ATR) inhibitor, which is thought to have synergy with the chemotherapy agents via the disruption of DNA repair.
The study recruited patients who had not undergone cytotoxic therapy for metastatic disease or platinum-based chemotherapy in the past year, but were eligible for cisplatin treatment, he explained.
The 46 patients randomly assigned to receive berzosertib 90 mg/m2 on days 2 and 9 of each 21-day cycle received an attenuated chemotherapy regimen of cisplatin 60 mg/m2 on day 1 and gemcitabine 875 mg/m2 on days 1 and 8, whereas the 41 patients given chemotherapy alone received a standard regimen of cisplatin 70 mg/m2 on day 1 and gemcitabine 1000 mg/m2 on days 1 and 8.
The presenter described the study arms as “relatively well balanced,” comprising mainly White men with a Bajorin risk score of 1 or 2. Around half of the participants had visceral metastases and 10% had a history of neoadjuvant cisplatin use.
The primary endpoint of median PFS was a comparable 8 months for both treatment arms.
Moreover, the overall survival (OS) findings were “somewhat concerning,” Pal said, noting that the curves separated early and the nonsignificant hazard ratio of 1.33 favored the control arm, with a numerically lower median OS of 14.4 months with berzosertib plus chemotherapy versus 19.8 months with chemotherapy alone.
And subset analysis by age, sex, Karnofsky performance status, and Bajorin risk group did not identify any patient groups who derived a PFS or OS benefit from the addition of the ATR inhibitor to chemotherapy, the presenter emphasized.
The response rate was also lower in the combination arm, at 54% versus 63% with chemotherapy only, including for the rates of complete responses, at 8.7% versus 9.8%.
Discussing the toxicity data, Pal highlighted that the combination arm participants experienced a higher rate of grade 3–4 thrombocytopenia than patients given only chemotherapy (59 vs 39%), as well as more neutropenia of this severity (37 vs 27%).
The rates of dose reduction with the ATR inhibitor plus chemotherapy were higher than those required for the chemotherapy-only arm for both cisplatin (34.8 vs 34.2%) and gemcitabine (60.9 vs 53.7%), despite patients given berzosertib already receiving attenuated chemotherapy doses, the presenter noted. Berzosertib-treated patients also required greater use of growth factors (50.0 vs 34.1%).
“This ultimately translated to a much lower cumulative dose of cisplatin on the experimental arm,” Pal continued, with a significant difference in the median doses given of 250 versus 370 mg/m2, reduced from the intended doses of 360 and 420 mg/m2, respectively.
“In my opinion, it’s this compromised dosing of cytotoxic therapy that might potentially account for the concerning trends in overall survival that we observed in this study,” the presenter concluded.
“This perhaps serves as fodder for further discussion as we plan our other trials in metastatic urothelial cancer and our data suggests our dosage of cytotoxic therapy, perhaps especially cisplatin, should not be compromised.”
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This independent news story was supported by an educational grant from Pfizer and Merck Healthcare KGaA, Darmstadt, Germany