Study Suggests Berzosertib Does Not Benefit Metastatic Bladder Cancer Patients

A recent City of Hope study claims a therapy that combines a drug that disrupts DNA repair with chemotherapy cisplatin and gemcitabine does not prolong progression-free survival for patients with urothelial cancer.

Adding the novel ataxia telangiectasia and Rad3-related (ATR) inhibitor drug berzosertib to standard-of-care chemotherapy for patients with metastatic urothelial cancer does not extend progression-free survival, according to a Phase 2 trial led by City of Hope, research and treatment center for cancer and diabetes.

Chemotherapy drugs cisplatin and gemcitabine are typically given to people with cancer cells that line the urethra, bladder, ureters and renal pelvis. Yet, cisplatin-based therapies do not cure these patients, and attempts to combine with novel therapies have failed to extend survival. It was thought that adding the ATR inhibitor drug berzosertib, which disrupts DNA damage repair and induces tumor cell death, could increase the efficacy of current therapies, according to a release by City of Hope.

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

The Phase 2 study was published recently in JAMA Oncology and included 87 patients across 23 cancer centers affiliated with the National Cancer Institute. The control arm received cisplatin with gemcitabine alone, and the experimental arm received the same treatment plus berzosertib. Patients were followed for up to three years.

Median progression-free survival for both groups was eight months, but inferior overall survival was observed in the experimental group. An estimated 83,730 people will be diagnosed with bladder cancer and some 17,200 people will die from the disease this year, according to the American Cancer Society. About 9 out of 10 people with bladder cancer over 55 years old, the release said.

“One challenge with berzosertib is that when combined with chemotherapy, it greatly decreases a patient’s white blood cells and platelets,” Pal said.

Future efforts should focus on biomarker-based treatment options that could help identify which patients would benefit most from either monotherapy or rational combinations with less negative impact on bone marrow, the release said.

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

According to a clinical study for the 2019 FDA approved Urothelial Cancer treatment, Padcev, an approved drug meant to treat locally advanced or metastatic urothelial cancer in certain adults who've received both treatment with chemotherapy or a programmed death receptor or ligand, this treatment has been responding to the cancer in patients.

In the study, 125 adults with locally advanced or urothelial cancer were given Padcev and results showed 44% of people had the cancer respond.

It isn’t yet known whether Padcev improves overall survival or if it increases the length of time that some people live without their cancer progressing. However, data further showed 12% of people had a complete response to treatment. This meant certain tests no longer detected cancer in their body, but doesn’t necessarily mean that the cancer is cured.

Further testing remains ongoing for each treatment.