Selective ATR Inhibitor Combined with Chemotherapy in Patients with Urothelial Cancer - Expert Commentary

Platinum-based chemotherapy remains the cornerstone for the first-line treatment of platinum-eligible patients with advanced urothelial cancer. Chemotherapy combinations with other agents did not improve survival in the front-line setting.  It is unclear if targeting DNA damage repair pathways augments the efficacy of cisplatin-based chemotherapy.

A recently published study by Pal et al. in JAMA Oncology investigated the addition of berzosertib, an ATR inhibitor, to standard-of-care chemotherapy in patients with advanced urothelial cancer. The study randomized 87 patients to either cisplatin with gemcitabine alone (control arm) or cisplatin with gemcitabine plus berzosertib (experimental arm). An initial dose reduction was applied to cisplatin and gemcitabine in the experimental arm to avoid myelosuppression. Eligible patients recieved no prior systemic treatment for their metastatic disease. The median follow-up was 18.9 months. The median age of the study population was 67 (range, 32-84) years. The primary endpoint was progression-free survival (PFS). Bajorin risk criteria were used for stratification. 

A total of 46 patients enrolled in the experimental arm and 41 patients in the control arm. The median PFS was similar in both arms (8 months, stratified hazard ratio (HR) was 1.22 (95% CI, 0.72- 2.08). There was a trend for lower median overall survival was in the experimental arm compared to the control arm (14.4 vs. 19.8 months, Bajorin-adjusted HR 1.42 (95% CI, 0.76-2.68). The median duration of therapy was similar between two arms, and approximately half of the patients in each arm were able to complete 6 cycles of treatment. The overall response rate was 54% in the experimental arm and 63% in the control arm. The cumulative rate of grade 3/4 adverse events was significantly higher in the experimental compared to the control arm (42/46 (91%) vs. 27 of 41 (66%), P < 0.01). Patients in the berzosertib arm had a median cisplatin dose of 250 mg/m2, which was significantly lower than the median dose of 370 mg/m2 in arm A (P < .001)

While the synergy between berzosertib and chemotherapy was shown in preclinical studies. Also, the addition of berzosertib to chemotherapy showed promising results in ovarian cancer compared to chemotherapy alone. However, there was a trend toward inferior survival in the berzosertib arm compared to chemotherapy alone in patients with urothelial cancer. Potential explanations for these unexpected results include the lower median dose of cisplatin in the berzosertib and the lack of patient selection for DDR gene alterations.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York

References:

  1. Pal SK, Frankel PH, Mortazavi A, Milowsky M, Vaishampayan U, Parikh M, et al. Effect of Cisplatin and Gemcitabine With or Without Berzosertib in Patients With Advanced Urothelial Carcinoma. JAMA Oncol. 2021 Aug 26;91010: doi.10.1001/jamaoncol.2021.3441.
  2. Konstantinopoulos PA, Cheng S-C, Wahner Hendrickson AE, Penson RT, Schumer ST, Doyle LA, et al. Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2020 Jul;21(7):957–68.

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