Effect of Cisplatin and Gemcitabine With or Without Berzosertib in Patients With Advanced Urothelial Carcinoma: A Phase 2 Randomized Clinical Trial

Abstract

Importance: Preclinical studies suggest that inhibition of single-stranded DNA repair by ataxia telangiectasia and Rad3 (ATR) may enhance the cytotoxicity of cisplatin, gemcitabine, and other chemotherapeutic agents. Cisplatin with gemcitabine remains the standard up-front therapy for treatment in patients with metastatic urothelial cancer.

Objective: To determine whether the use of the selective ATR inhibitor, berzosertib, could augment the activity of cisplatin with gemcitabine.

Design, setting, and participants: In a phase 2 randomized clinical trial, 87 patients across 23 centers in the National Cancer Institute Experimental Therapeutics Clinical Trials Network were randomized to receive either cisplatin with gemcitabine alone (control arm) or cisplatin with gemcitabine plus berzosertib (experimental arm). Key eligibility criteria included confirmed metastatic urothelial cancer, no prior cytotoxic therapy for metastatic disease, 12 months or more since perioperative therapy, and eligibility for cisplatin receipt based on standard criteria. The study was conducted from January 27, 2017, to December 15, 2020.

Interventions: In the control arm, cisplatin, 70 mg/m2, was given on day 1 and gemcitabine, 1000 mg/m2, was given on days 1 and 8 of a 21-day cycle. In the experimental arm, cisplatin, 60 mg/m2, was given on day 1; gemcitabine, 875 mg/m2, on days 1 and 8; and berzosertib, 90 mg/m2, on days 2 and 9 of a 21-day cycle.

Main outcomes and measures: The primary end point of the study was progression-free survival. The analysis was on all patients who started therapy.

Results: Of the total of 87 patients randomized, 41 patients received cisplatin with gemcitabine alone and 46 received cisplatin with gemcitabine plus berzosertib. Median age was 67 (range, 32-84) years, and 68 patients (78%) were men. Median progression-free survival was 8.0 months for both arms (Bajorin risk-adjusted hazard ratio, 1.22; 95% CI, 0.72-2.08). Median overall survival was shorter with cisplatin with gemcitabine plus berzosertib compared with cisplatin with gemcitabine alone (14.4 vs 19.8 months; Bajorin risk-adjusted hazard ratio, 1.42; 95% CI, 0.76-2.68). Higher rates of grade 3 vs grade 4 thrombocytopenia (59% vs 39%) and neutropenia (37% vs 27%) were observed with cisplatin with gemcitabine and berzosertib compared with cisplatin with gemcitabine alone; consequently, more dose reductions were needed in the experimental arm. Patients in the experimental arm received a median cisplatin dose of 250 mg/m2, which was significantly lower than the median dose of 370 mg/m2 in the control arm (P < .001).

Conclusions and relevance: The addition of berzosertib to cisplatin with gemcitabine did not prolong progression-free survival relative to cisplatin with gemcitabine alone in patients with metastatic urothelial cancer, and a trend toward inferior survival was observed with this combination. Berzosertib plus cisplatin with gemcitabine was associated with significantly higher hematologic toxicities despite attenuated dosing of cisplatin with gemcitabine.

Trial registration: ClinicalTrials.gov Identifier: NCT02567409.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Pal reported receiving fees for serving on the advisory boards of Pfizer, Novartis, Aveo, Genentech, Exelixis, Bristol-Myers Squibb, Astellas Pharma, Roche, and Ipsen outside the submitted work. Dr Mortazavi reported other from NIH. The study was an NIH-sponsored trial, and supported by our institutional UM1 NIH Grant during the conduct of the study; research funding to the institution from Acerta Pharma, Genentech, Roche, Merck Novartis, Seattle Genetics, Astellas Pharma, Mirati Therapeutics, Bristol-Myers Squibb, and Debiopharm Group; and fees for serving on the advisory boards of Seattle Genetics, Pfizer, and Debiopharm Group outside the submitted work. Dr Milowsky reported receiving grants to the institution from Merck, Roche/Genentech, Bristol-Myers Squibb, Astellas Pharma, Clovis Oncology, Inovio Pharmaceuticals, Mirati Therapeutics, Constellation Pharmaceuticals, Syndax, Incyte, Amgen, Regeneron, Arvinas, Seagen, Pfizer, and Johnson & Johnson/Janssen outside the submitted work. Dr Vaishampayan reported receiving personal fees from BMS, Exelixis, Bayer, Sanofi, Genentech, AAA, and Alkermes, and grants from Merck and Astellas outside the submitted work. Dr M. Parikh reported receiving consulting fees from Janssen, Oncocyte, and Seagen outside the submitted work. Dr Lyou reported receiving personal fees from Pfizer and Seattle Genetics outside the submitted work. Dr Teply reported receiving personal fees from AstraZeneca and Janssen outside the submitted work. Dr Dreicer reported receiving personal fees from Astellas, Bayer, Eisai, EMD, Serono, Exelixis, GIlead, Hinova, Infinity, Janssen, Merck, Myovant, Pfizer, Propella, and Tavanta outside the submitted work. Dr Emamekhoo reported receiving consulting fees from BMS, Exilexis, Seattle Genetics, and Bayer outside the submitted work. Dr Zhang reported receiving grants from NCI UM1 during the conduct of the study; grants from Genentech, Pfizer, Janssen, Acerta, Abbvie, Novartis, Merrimack, OmniSeq, PGDx, Merck, Mirati, Astellas, and Regeneron; personal fees from Exelixis, Genomic Health, Sanofi Aventis, and Astra Zeneca, Bayer, Foundation Medicine, Amgen, MJH Associates, Merck, Bristol-Myers Squibb, Pharmacyclics, SeaGen, Calithera, and Dendreon outside the submitted work; and spouse is cofounder and stockholder of both Capio Biosciences and Archimmune Therapeutics. Dr Kim reported holding stock and having other ownership interests in Abbvie, Abbott, Amgen, Arvinas, BeiGene, Bristol-Myers Squibb, Bluebird Bio, FibroGen, Illumina, Johnson & Johnson, Myovant, Natera, Oramed, Syndax, and Zentalis; receiving consulting or advisory fees from H3 Biomedicine, Takeda; Foundation Medicine, and GeneCentric; receiving research funding from Acerta, Foundation Medicine, GeneCentric, and Merck; and fees for travel, accommodations, and expenses from H3 Biomedicine and Takeda. No other disclosures were reported.

Figures

Figure 1.. Consolidated Standards of Reporting Trials Diagram

Figure 2.. Analysis of Survival

A, Progression-free survival, P = .55; hazard ratio (HR), 1.17 (95% CI, 0.69-1.98). B, Overall survival, P = .37; HR, 1.33 (95% CI, 0.71-2.48). The HR was not adjusted for Bajorin risk criteria.

Figure 3.. Cumulative Dose of Cisplatin in Patients Receiving Cisplatin and Gemcitabine With Berzosertib (Arm A) and Cisplatin and Gemcitabine Alone (Arm B)

Median doses are indicated with the horizontal bars; error bars represent interquartile ranges; each dot represents 1 patient. Median cisplatin dose was 250 mg/m2 in patients also receiving gemcitabine and berzosertib and 370 mg/m2 in those not receiving berzosertib. The single largest value in arm A represents a deviation in 1 patient who received the higher arm B dose of cisplatin for 2 cycles and completed all 6 cycles on arm A.