A Hoosier Cancer Research Network multi-site phase II study led by Icahn School of Medicine at Mount Sinai/Tisch Cancer Institute is testing the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib in metastatic urothelial cancer patients with somatic DNA damage response (DDR) alterations in their cells. The study is open to accrual at HCRN member sites, including: Barbara Ann Karmanos Cancer Center in Detroit, Mich.; Huntsman Cancer Institute in Salt Lake City, Utah; Icahn School of Medicine at Mount Sinai in New York, N.Y.; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, Md.; The University of Chicago Medicine Comprehensive Cancer Center in Chicago, Ill; and the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, N.C.

Urothelial cancer forms in cells that line the urethra, bladder, renal pelvis, and ureters. Bladder tumors often have mutations in genes involved in repair of DNA damage.

“We know in urothelial cancer that, based on genomic sequence studies that have been done, a lot of mutations occur in these DNA damage repair genes, but it has never really been tested whether or not these gene mutations in bladder cancer render tumors more susceptible to these drugs called PARP inhibitors,” said Matthew D. Galksy, MD, sponsor-investigator of the study and a medical oncologist at Mount Sinai.

Standard treatment for metastatic urothelial cancer includes platinum-based chemotherapy or immune checkpoint blockade with PD-1 or PD-L1 antibodies. However, not all patients will benefit from these treatments, and researchers are investigating new approaches.

The study, HCRN-GU15-262, “Phase 2 Trial of Olaparib in Patients with Metastatic Urothelial Cancer Harboring DNA Damage Response Gene Alterations,” will estimate objective response rate, the proportion of patients whose tumors shrink during the study; and evaluate progression-free survival, or how long it takes before the tumors start growing again.

Olaparib is approved by the U.S. Food & Drug Administration (FDA) as a first-line maintenance therapy for BRCA-mutated advanced ovarian cancer; for the treatment of germline BRCA-mutated metastatic breast cancer; and for the maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. Olaparib is not FDA-approved to treat urothelial cancer and should be considered investigational.

“This is a drug that has been tested pretty extensively in terms of the safety and tolerability,” Dr. Galsky said. “What we’re trying to do here is see if it works in urothelial cancer.”

In other types of cancer, when cancer cells with mutations in DNA damage repair genes are exposed to PARP inhibitors, the cancer cells die due to a phenomenon known as synthetic lethality, Dr. Galsky added.

“In other types of cancer, most notably ovarian cancer and breast cancer, it’s been shown that some cancer cells have mutations or defects in genes that are involved in repairing DNA damage,” he said. “Whenever there’s a process that’s replicated so many times, there’s inherently going to be some damage that can occur. As those genes that are involved in repairing damage get damaged themselves, the cells acquire more mutations, because they can’t repair the damage that’s naturally occurring as cells are copying their DNA and dividing.”

By putting stress on a cell that already has impairment in repairing damage, Dr. Galsky said, “then that might cause enough stress for it to be lethal to the cell. PARP inhibitors cause DNA damage. If you give them to a normal cell, not a lot happens because cells have this machinery to repair DNA damage, but if you give PARP inhibitors to a cell that already has an error in its DNA damage repair mechanisms, then it kills the cell.”

The study will enroll up to 30 participants. To qualify, participants must be adults age 18 and older, with metastatic urothelial cancer harboring somatic DNA damage response (DDR) alterations, as determined by genomic sequencing.

All study participants will receive olaparib. Subjects may continue taking olaparib until their cancer worsens or side effects become intolerable. Participants may withdraw from the study at any time in consultation with their doctor.

Blood and tissue will be collected to support correlative research.

The study is supported by AstraZeneca.

For more information about this research study, including full eligibility requirements, visit www.clinicaltrials.gov (study #NCT03448718).

About Hoosier Cancer Research Network:

Hoosier Cancer Research Network (formerly known as Hoosier Oncology Group) conducts innovative cancer research in collaboration with academic and community physicians and scientists across the United States. The organization provides comprehensive clinical trial management and support, from conception through publication. Created in 1984 as a program of the Walther Cancer Institute, Hoosier Cancer Research Network became an independent nonprofit clinical research organization in 2007. Since its founding, Hoosier Cancer Research Network has conducted more than 210 trials in a variety of cancer types and supportive care, resulting in more than 350 publications. More than 8,500 subjects have participated in Hoosier Cancer Research Network clinical trials.