Berzosertib/Chemo Combo Misses PFS End Point in Metastatic Urothelial Cancer

Sumanta K. Pal, MD

The addition of berzosertib to standard cisplatin/gemcitabine did not improve progression-free survival (PFS) compared with chemotherapy alone in patients with metastatic urothelial cancer, according to results of a phase 2 trial (NCT02567409) that were published in JAMA Oncology.¹

Results showed that there was no significant difference in PFS between the 2 arms, at 8.0 months with both the berzosertib (95% CI, 6.8- NA months) and chemotherapy-alone arms (95% CI, 6.0-14.4 months; Bajorin risk-adjusted HR, 1.22; 95% CI, 0.72-2.08). However, the median overall survival (OS) was 14.4 months (95% CI, 10.0-NA) with chemotherapy/berzosertib and 19.8 months (95% CI, 14.8-NA) with chemotherapy alone (Bajorin risk-adjusted HR, 1.42; 95% CI, 0.76-2.68), demonstrating inferior survival with the berzosertib arm.

“It’s important to report trials with a null result,” said lead investigator Sumanta K. Pal, MD, clinical professor in the Department of Medical Oncology & Therapeutics Research, City of Hope.² “If we don’t do cautionary phase 2 trials, we may end up investing finances and people’s lives in larger phase 3 clinical trials without seeing any tangible gains in patient survival.”

Cisplatin plus gemcitabine is the standard frontline therapy for patients with urothelial cancer. Berzosertib is an ataxia telangiectasia and Rad3 (ATR) inhibitor, and preclinical findings suggest that ATR inhibition of single-stranded DNA repair could enhance cisplatin’s cytotoxicity, gemcitabine, and other types of chemotherapies.

In a phase 1 study of berzosertib of 40 patients with advanced cancers, 17 patients received single-agent berzosertib while 23 were given berzosertib plus carboplatin.³ Data showed that 1 patient with advanced colorectal cancer who received berzosertib alone had a complete response lasting 29 months; many patients experienced stable disease as the best response.

We know that chemotherapy damages DNA. Cancer cells can outsmart this process by repairing DNA damage,” Pal added. “Many experts thought berzosertib could disrupt that system and prevent cancer cells from repairing their damaged DNA.”

In the open-label, phase 2 trial, 87 patients with metastatic urothelial cancer across 23 National Cancer Institute–affiliated cancer centers were randomized to receive cisplatin/gemcitabine with or without berzosertib. In the experimental arm (n = 46), berzosertib was given at 90 mg/m² on days 2 and 9 over 1 hour, cisplatin at 60 mg/m² on day 1, and gemcitabine at 875 mg/m² on days 1 and 8 of a 21-day cycle. In the standard-therapy arm (n = 41), cisplatin was given at 70 mg/m² on day 1 and gemcitabine at 1000 mg/m² on days 1 and 8 of a 21-day cycle.

Patients who were aged 18 years or older had to have histologically or cytologically confirmed metastatic urothelial cancer with measurable disease, a Karnofsky performance status greater than or equal to 70%, a life expectancy of at least 6 months, were eligible for cisplatin, could not have had cytotoxic therapy for their metastatic disease, and at least 1 year must have passed since platinum-based perioperative treatment was administered. Patients could not have had symptomatic congestive heart failure or preexisting neuropathy.

A stratification factor was Bajorin risk category (0 = KPS ≥80 and no visceral metastases; 1 = KPS <80 or visceral metastases [but not both]; and 2 = both KPS <80 and presence of visceral metastases).

After baseline imaging, patients were measured for response every 9 weeks for 6 months and followed by every 12 weeks.

The primary end point was PFS in the overall study population. Patients were followed for up to 3 years.

The median age was 67 years (range, 32-84) and 78% (n = 68) were men. Most patients (85%) were White; the Karnofsky performance status was 90% to 100% in two-thirds of the overall population. Four patients, 2 in each arm, had a Karnofsky performance status level of 70%.

The data cutoff date was December 15, 2020, and the median follow-up of 18.9 months (IQR, 9.9-27.4). The median duration of treatment was 3.9 months (IQR, 2.3-4.2 months) for chemotherapy alone and 3.7 months (IQR, 2.0-4.3 months).

The objective response rate was 63% with chemotherapy alone, with a 9.8% CR rate; these rates were 54% and 8.7% with the addition of berzosertib.

Regarding safety, grade 3/4 adverse events was found to be significantly higher with cisplatin/gemcitabine plus berzosertib vs cisplatin/gemcitabine alone, at 91% vs 66%, respectively (P < .01). Moreover, the addition of berzosertib had higher rates of grade 3/4 thrombocytopenia at 59% vs 39% with chemotherapy alone, as well as grade 3/4 neutropenia at 37% and 27%, respectively.

The berzosertib arm also required more dose reductions than the chemotherapy-alone arm. The median cisplatin doses were 250 mg/m² vs 370 mg/m² (P <.001).

Next steps should focus on biomarker-driven studies evaluating combination regimens that have a reduced negative impact on patients’ bone marrow, the authors concluded.

References

1. Pal SK, Frankel PH, Mortazavi A, et al. Effect of cisplatin and gemcitabine with or without berzosertib in patients with advanced urothelial carcinoma: a Phase 2 Randomized Clinical Trial. JAMA Oncol. Published online August 26, 2021. doi:10.1001/jamaoncol.2021.3441
2. City of Hope study suggests adding the drug berzosertib to standard treatment for metastatic bladder cancer does not benefit patients. News release. City of Hope. August 26, 2021. Accessed August 27, 2021. https://bit.ly/3BjiO3j
3. Yap TA, O’Carrigan B, Penney MS, et al. Phase I trial of first-in-class ATR inhibitor M6620 (VX-970) as monotherapy or in combination with carboplatin in patients with advanced solid tumors. J Clin Oncol. 2020;38(27):3195-3204. doi:10.1200/JCO.19.02404