Novel ATR inhibitor berzosertib falls short in advanced urothelial cancer

Adding the ATR inhibitor berzosertib to standard cisplatin/gemcitabine (CG) did not improve progression-free or overall survival (OS) in patients with advanced urothelial cancer, according to findings from a phase 2 trial presented at the 2021 ASCO Annual Meeting.1

The median OS was 14.4 months with the addition of berzosertib versus 19.8 months with CG alone (HR, 1.33; 95% CI, 0.71-2.48; P = .374). The median progression-free survival (PFS) was 8 months in both study arms (HR, 1.17; 95% CI, 0.69-1.98; P = .553).

To enroll on the phase 2 trial patients had to have histologically or cytologically confirmed metastatic disease and be cisplatin eligible. Prior cytotoxic therapy for metastatic disease was not allowed and at least 12 months must have passed since the patient received any platinum-based perioperative treatment.

The study included 91 patients who were enrolled between January 27, 2017, and December 12, 2019. Three patients withdrew consent prior to starting treatment and 1 patient no longer met eligibility criteria, leaving 87 patients who were randomized. Of these patients, 41 were randomized to CG and 46 were randomized to CG plus berzosertib.

Patient characteristics were well balanced between the 2 study arms. In the berzosertib arm, the median age was 67.5 years (range, 32-82), 83% were male, 85% were White, and 48% had visceral metastases.The Bajorin risk group was 0 for 50% of patients, 1 for 43%, and 2 for 7%. Eleven percent of patients had received prior neoadjuvant cisplatin.

In the CG arm, the median age was 65 years (range, 32-84), 73% were male, 85% were White, and 46% had visceral metastases. The Bajorin risk group was 0 for 54% of patients and 1 for 46%. Ten percent of patients had received prior neoadjuvant cisplatin.

Patients were randomized in a 1:1 ratio to either cisplatin (70 mg/m2) on day 1 and gemcitabine (1000 mg/m2) on days 1 and 8 of 21-day cycles, or berzosertib (90 mg/m2) on days 2 and 9 of 21-day cycles plus cisplatin at 60 mg/m2 on day 1 and gemcitabine at 875 mg/m2 on days 1 and 8.

“I think it’s important to point out that on the experimental arm we used attenuated doses of cisplatin and gemcitabine,” said lead author Sumanta K. Pal, MD, FASCO, medical oncologist and assistant clinical professor in the Department of Medical Oncology and Therapeutics Research at City of Hope.

Treatment was administered for a maximum of 6 cycles. The primary end point was PFS. Secondary end points included response, OS, and safety.

The researchers conducted a subset analyses of OS and PFS and found that, “Across strata of age, gender, Karnofsky performance status, and Bajorin risk, we did not identify any groups that preferentially benefitted from the addition of berzosertib to cisplatin and gemcitabine,” said Pal.

The response rate was 63% with CG alone compared with 54% with the addition of berzosertib. The complete response rates were 9.8% versus 8.7%, respectively.

Regarding safety, grade 1/2 adverse events (AEs) occurring in the berzosertib arm were platelet count decreased (17%), neutrophil count decreased (17%), white blood cells decreased (13%), lymphocyte count decreased (20%), hyperglycemia (4%), hyponatremia (26%), acute kidney injury (4%), anemia (26%), hypokalemia (4%), urinary tract infection (7%), dehydration (4%), dyspnea (11%), thromboembolic event (2%), fatigue (57%), abdominal pain (7%)

hypomagnesemia (22%), edema limbs (15%), hypoalbuminemia (11%), nausea/vomiting (59%), anorexia (20%), generalized muscle weakness (15%) hyperkalemia (9%), and hypertension(4%).

“About 59% of patients had grade 3/4 thrombocytopenia in association with cisplatin/gemcitabine plus berzosertib. This was in contrast to a rate of grade 3/4 cytopenia of 39% with cisplatin and gemcitabine alone…There was also a 37% rate of grade 3/4 neutropenia with the combination of cisplatin, gemcitabine, and berzosertib, in contrast to a rate of 27% with cisplatin and gemcitabine alone,” said Pal.

The rate of dose reductions for cisplatin was about 34% in both arms. The rate of dose reduction for gemcitabine was 60.9% versus 53.7% in the treatment versus control arms, respectively. In the treatment arm, 19.6% of patients required a dose reduction of berzosertib. Growth factors were used in 50% of the berzosertib arm versus 34.1% of the control arm.

Pal noted that cumulative doses of cisplatin were significantly lower in the berzosertib arm.

“Compromised delivery of cytotoxic chemotherapy may account for the concerning trends in OS observed in this study,” Pal said in his concluding remarks.

Reference

1. Pal SK, Mortazavi A, Milowsky MI, et al. A randomized phase II study comparing cisplatin and gemcitabine with or without berzosertib in patients with advanced urothelial carcinoma. J Clin Oncol 39, 2021 (suppl 15; abstr 4507). doi: 10.1200/JCO.2021.39.15_suppl.4507