Effect of Cisplatin and Gemcitabine With or Without Berzosertib in Patients With Advanced Urothelial Carcinoma

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 PARTICIPANTSIn 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. INTERVENTIONSIn the control arm, cisplatin, 70 mg/m 2 , was given on day 1 and gemcitabine, 1000 mg/m 2 , was given on days 1 and 8 of a 21-day cycle. In the experimental arm, cisplatin, 60 mg/m 2 , was given on day 1; gemcitabine, 875 mg/m 2 , on days 1 and 8; and berzosertib, 90 mg/m 2 , on days 2 and 9 of a 21-day cycle. MAIN OUTCOMES AND MEASURESThe primary end point of the study was progression-free survival. The analysis was on all patients who started therapy. RESULTSOf 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/m 2 , which was significantly lower than the median dose of 370 mg/m 2 in the control arm (P < .001). CONCLUSIONS AND RELEVANCEThe 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 g...

Therapeutic Targeting of DNA Damage Response in Cancer

“…In a phase 2 trial for urothelial carcinoma therapy, berzosertib was added to gemcitabine and cisplatin as first-line treatment and compared with chemotherapy alone; PFS was not significantly different between the berzosertib group vs. chemotherapy alone (8.0 months for both arms), but overall survival (OS) was shorter in the berzosertib group (14.4 months vs. 19.8 months). The combination arm also had higher rates of serious adverse events, which were mostly related to myelosuppression [56]. Although the results of ongoing studies are anticipated, these phase 2 trial results imply that combination strategies should be optimized for the selection of partner drugs and target patients (Table 1).…”

Everything Comes with a Price: The Toxicity Profile of DNA-Damage Response Targeting Agents

“…In phase I trials testing ATR inhibitors berzosertib and ceralasertib with chemotherapy, hematological AEs (neutropenia, anemia and thrombocytopenia), fatigue and emesis were the most common toxicities [ 22 , 96 , 97 , 98 ]. Two randomized phase II studies confirmed that the addition of berzosertib to gemcitabine in ovarian cancer patients and to cisplatin/gemcitabine in urothelial cancer patients increased the incidence and severity of hematological toxicities and the rate of nausea and vomiting [ 21 , 87 ].…”

Molecularly Targeted Therapy towards Genetic Alterations in Advanced Bladder Cancer

“…Among patients with lenvatinib, 7% were noted to develop cardiac dysfunction, with 2% noting grade 3 or greater. In addition to multi-kinase inhibitors, berzosertib, an inhibitor of ataxia telangiectasia and Rad3-related (ATR) protein, was evaluated in addition to chemotherapy in patients with metastatic UC who had not yet received chemotherapy for metastatic disease [ 169 ]. Unfortunately, there was no improvement in progression-free survival.…”