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Somatic alterations in DNA damage response (DDR) genes are common in advanced urothelial cancer, and researchers are now exploring the effectiveness of poly-ADP ribose polymerase (PARP) inhibitors in select patients with these alterations.

Matthew Galsky, MD, of Tisch Cancer Institute in New York City, and colleagues evaluated the activity of olaparib in a small group of patients with metastatic urothelial cancer and somatic DDR alterations who had disease progression on platinum chemotherapy. Although the results were not promising, the study provided some useful information, the team noted in

Of the 19 participants, none had a complete or partial response, but six had stable disease lasting 2 to 16 months (median about 8 months). Median progression-free survival was 1.9 months (range 0.8-16 months), and median overall survival was 9.5 months (range 1.5-22 months).

"Despite the relatively high prevalence of DDR gene alterations in urothelial cancer, single-agent PARP inhibition in the setting of predominantly platinum-resistant disease demonstrates negligible clinical activity," the researchers concluded.

However, they noted, the results of their study and others suggest that PARP inhibition may have activity in some patients with advanced urothelial cancer, although identifying those patients will be challenging.

Galsky, director of Genitourinary Medical Oncology, co-director of the Center of Excellence for Bladder Cancer, and associate director for Translational Research, discussed this and other issues in the following interview.

Your paper noted that the trial closed early because of slow accrual, and that therefore the sample size was small. Why was the accrual slow?

Galsky: Metastatic urothelial cancer is not the most common malignancy. Unfortunately, given the biology of the disease, we know that only a subset of patients with metastatic urothelial cancer will be able to receive third- or fourth-line therapy. Couple that with a trial that is enrolling a molecularly selected population and an investigator-initiated trial being conducted at a limited number of centers, that can create enrollment challenges.

However, we believed the question we were posing was critically important, had not been previously addressed, and therefore felt it was important to try and generate this data.

Your paper also said the lack of response could have been due to previous exposure to platinum-based chemotherapy. Why was that?

Galsky: We think there may be some cross-resistance between platinum chemotherapy and PARP inhibition, and the vast majority of patients enrolled in our trial had received prior platinum-based chemotherapy.

The genomic alterations that confer sensitivity to PARP inhibitors in patients with urothelial cancer are not well defined. How can researchers identify patients with the best alterations to target?

Galsky: This is both a pre-clinical and a clinical issue. From a pre-clinical standpoint, making some of these less common mutations and introducing them into bladder cancer cells to see if this leads to synthetic lethality with PARP inhibition could be important.

From a clinical standpoint, we need to learn from other malignancies where much larger studies have been completed to understand which genes when mutated do indeed confer sensitivity to PARP inhibition versus those that are just hypothesized to confer sensitivity. Such lessons have been learned in prostate cancer through large-scale clinical trials.

Do you have any more research planned or ongoing in this area?

Galsky: We, and others, are seeking to determine whether newer drugs targeting proteins involved in DNA damage response and repair may be more active in urothelial cancer.

Read the study here.