Berzosertib Does Not Extend PFS in Metastatic Urothelial Cancer

Adding berzosertib, a novel ataxia telangiectasia and Rad3-related inhibitor drug, to standard-of-care chemotherapy does not extend progression-free survival for patients with metastatic urothelial cancer.

Adding berzosertib, a novel ataxia telangiectasia and Rad3-related inhibitor (ATR) drug, to standard-of-care chemotherapy does not extend progression-free survival (PFS) for patients with metastatic urothelial cancer (mUC), according to a recent phase 2 study conducted by the City of Hope Cancer Comprehensive Center.1

The current standard of care chemotherapy for mUC is cisplatin and gemcitabine. This combination is typically given to people with cancer cells in the urethra, bladder, ureters, and renal pelvis. However, these cisplatin-based therapies do not cure patients and novel combination therapies have failed to extended survival. It was believed that adding an ATR inhibitor like berzosertib would disrupt DNA damage repair while also inducing tumor cell death, thus increasing the efficacy of current therapies.1

“We know that chemotherapy damages DNA. Cancer cells can outsmart this process by repairing DNA damage,” said Sumanta Pal, MD, clinical professor in City of Hope’s Department of Medical Oncology & Therapeutics Research, in a press release. “Many experts thought berzosertib could disrupt that system and prevent cancer cells from repairing their damaged DNA.”

The randomized, parallel assignment study has an estimated enrollment of 90 participants and an estimated primary completion date of August 31, 2021. The primary end point is PFS. Secondary end points include overall survival (OS), overall response rate (ORR), incidence of toxicities, and analysis of potential predictors of response.2

Patients were randomized 1:1 to either receive the standard of care chemotherapy regimen alone or in combination with berzosertib. Dose reductions were allowed. Patients continued treatment for a total of 6 cycles unless early discontinuation was warranted due to disease progression, intercurrent illness, unacceptable adverse events (AEs), or patient withdrawal.3

Ultimately, 87 patients were randomized into 1 of 2 arms. The control arm had 41 patients and the experimental arm had 46 patients. The median age of the study population was 67, 78% were men, and 85% were white. There were only 2 patients in each arm with a Karnofsky Performance Score level of 70%. The vast majority of patients had a KPS performance status of 90% to 100%.3

At the time of data cutoff, all patients had discontinued treatment. At the median follow-up of 18.9 months, the median PFS in both arms was 8 months. Additionally, the median OS was longer in the control arm at 19.8 months (95% CI, 14.8-NA months) compared with 14.4 months in the experimental arm (95% CI, 10.0-NA months). The median DOR in the control arm was 3.9 moths (interquartile range [IQR], 2.3-4.2 months) compared with 3.7 months in the experimental arm (IQR, 2.0-4.3 months).3

The control arm had a partial response (PR) rate of 63% (95% CI, 0.47-0.78 months) and a compete response (CR) rate of 9.8%. The control arm had a PR rate of 54% (95% CI, 0.39%-0.69%) and a CR of 8.7%.3

In terms of safety, 91% of patients in the experimental arm and 66% of patients in the control arm had grade 3/4 AEs. This was most notably in hematologic toxic events. The rate of grade 3/4 thrombocytopenia was 59% in the experimental arm and 39% in the control arm. Additionally, the experimental arm had a grade 3/4 neutropenia rate of 37% compared to 27% in the control arm.3

In order to participate, patients must be 18 years old or older, have confirmed mUC, have measurable disease, have access to archival tumor tissue, no prior cytotoxic chemotherapy for metastatic disease, a life expectancy greater than 3 months, and at least 12 months since last platinum-based peri-operative treatment. Patients with radiotherapy within 4 weeks of protocol therapy, receiving any other investigational agent, uncontrolled intercurrent illness, pregnancy, or grade 2 neutropenia or greater are not eligible to participate.2 

“The key is to focus on other novel treatments for bladder cancer in the domain of precision medicine and immunotherapy,” said Pal, in the press release. “It’s important to find therapies that improve patient outcomes beyond what we see with cisplatin alone, which is very modest.”

REFERENCES:
1.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 30, 2021. https://bit.ly/3t0U5O9.
2.Cisplatin and gemcitabine hydrochloride with or without berzosertib in treating patients with metastatic urothelial cancer. ClinicalTrials.gov. Accessed August 30, 2021. https://bit.ly/2WCD9BL.
3.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