“Prior to these two studies, smaller studies showed a lack of response to PARP [poly (ADP-ribose) polymerase] inhibitors in previously treated patients with urothelial cancer, both as monotherapy and in combinations,” said formal discussant of the BAYOU and ATLANTIS trials, Sandy Srinivas, MD, Professor of Medicine/Oncology at Stanford University School of Medicine, Palo Alto, California.

Sandy Srinivas, MD

“Take-away messages from the BAYOU trial include that it sets a benchmark for progression-free and overall survival for platinum-ineligible patients, and the study raises the question of whether it is possible that HRR [homologous recombination repair] mutations confer a worse prognosis in urothelial cancer. The combination of durvalumab/olaparib does have activity in patients with HRR-mutated disease compared with durvalumab alone, but it is unclear whether that would be superior to PARP monotherapy in patients with HRR-mutated disease. We will await the results of the monotherapy olaparib trial in biomarker-selected patients,” she stated.

Dr. Srinivas shared her thoughts on the ATLANTIS trial. “The final analysis of ATLANTIS for rucaparib as maintenance therapy in genomically selected patients shows a progression-free survival that is almost double that of placebo. Avelumab maintenance [in the JAVELIN 100 Bladder trial] set the standard for first-line therapy of urothelial cancer. One of the biggest challenges is selecting sensitivity to PARP inhibitors,” she said.

The ATLANTIS trial used loss of heterozygosity tests, and the BAYOU trial used a panel of 15 mutations, only half of which were found in the study population. There are two other approved tests—Myriad CDx and Foundation Medicine CDx—as well as several other assays.

What Next?

“The field is rich for urothelial cancer,” commented Dr. Srinivas. “There are many ongoing trials of PARP inhibitors as monotherapy or in combinations in various settings. These studies raise more questions than answers.” Questions regarding the use of PARP inhibitors in urothelial cancer include data on monotherapy, the optimal setting, use of blood or tissue for genetic analysis, and measuring germline or somatic mutations.

“We hope the list of targeted therapies gets longer and improves outcomes. There is a hint of activity for PARP inhibitors in HRR-mutated urothelial cancer,” she stated. 

DISCLOSURE: Dr. Srinivas has served as a consultant or advisor to AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Janssen Oncology, Merck, Novartis, and Seattle Genetics; and has received institutional research funding from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Exelixis, Genentech, Merck, and Seattle Genetics/Astellas.