Maintenance Rucaparib Following Chemotherapy for DNA Repair Deficiency Biomarker-Positive Urothelial Carcinoma

Simon J Crabb, PhD, MBBS, Southampton Experimental Cancer Medicine Centre, University of Southampton, United Kingdom, discusses a phase 2 trial evaluating poly ADP-ribose polymerase (PARP) inhibitor rucaparib in the maintenance setting for DNA repair deficiency biomarker-positive patients with urothelial carcinoma.

In this randomized, double-blinded trial, maintenance rucaparib following platinum-based chemotherapy was tolerable and extended the progression-free survival of DNA repair deficiency biomarker-selected patients with metastatic urothelial carcinoma. Based on these results, Dr Crabb stated, further investigation of PARP inhibition in this patient population is warranted.

Transcript:

Hello. I'm Professor Simon Crabb. I'm a medical oncologist and I work in Southampton in the United Kingdom. I'm going to talk today about the rucaparib randomized comparison within the ATLANTIS trial platform. This was an investigator-led study that we designed in the UK. The attempt here was to look at novel treatment options within biomarker-selected subsets of patients with advanced urothelial carcinoma. This trial is designed to offer treatment approaches in maintenance setting, after the use of platinum-based chemotherapy first line treatment of advanced urothelial carcinoma. Of note, this trial was undertaken before the data emerged for the use of immunotherapy with avelumab in the maintenance setting, so all of the comparisons that were undertaken in this study were done against placebo.

The rucaparib comparison was designed with the idea that patients who benefit from platinum-based chemotherapy have a clinical phenotype which has overlap with the phenotype for patients who may benefit from PARP inhibition. So we used a biomarker for selection that required patients to have either an alteration in one of 15 pre-specified genes relevant for DNA repair or to have a high genome-wide loss of heterozygosity, because there was evidence to suggest that may also be a way of selecting patients who may benefit from PARP inhibitors.

In this study, patients had completed 4 to 8 cycles of first-line platinum-based chemotherapy and had not progressed at that point. And we selected patients who had this biomarker and then randomized them between rucaparib and placebo until disease progression. The primary endpoint was progression-free survival, and we had secondary endpoints relating to overall survival, disease response, and safety. The study met its primary endpoint — there was an improvement in progression-free survival between those patients that received rucaparib, who had a median progression-free survival of 35 weeks, compared to 15 weeks for placebo. And that equated to a hazard ratio of 0.53.

We found that treatment was tolerable and followed the experience seen with rucaparib and indeed other PARP inhibitors in this disease. We have recently published the data in the Journal of Clinical Oncology, and we've recommended that further investigation would be warranted of PARP inhibition in urothelial carcinoma based on the results of this phase 2 study.

Source:

Crabb SJ, Hussain S, Soulis E, et al. A randomized, double-blind, biomarker-selected, phase II clinical trial of maintenance poly ADP-ribose polymerase inhibition with rucaparib following chemotherapy for metastatic urothelial carcinoma. J Clin Oncol. Published online August 12, 2022. doi:10.1200/JCO.22.00405.