In a phase II trial reported in the Journal of Clinical Oncology, Simon J. Crabb, BSc, MBBS, MRCP, PhD, and colleagues found that maintenance therapy with the poly (ADP-ribose) polymerase (PARP) inhibitor rucaparib vs placebo was associated with prolonged progression-free survival in patients with DNA repair deficiency biomarker–positive metastatic urothelial carcinoma without disease progression after first-line platinum-based chemotherapy.
Study Details
In the double-blind, multicenter, signal-seeking trial, 40 patients were randomly assigned between November 2017 and February 2021 to receive maintenance rucaparib at 600 mg twice daily (n = 20) or placebo (n = 20) beginning within 10 weeks after completion of four to eight cycles of chemotherapy. Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival in the intention-to-treat population. Statistical analysis targeted a hazard ratio (HR) of 0.5, with a one-sided α of .05 for rucaparib vs placebo.
Progression-Free Survival
Median follow-up was 94.6 weeks in surviving patients. Median progression-free survival was 35.3 weeks (80% confidence interval [CI] = 11.7–35.6 weeks) in the rucaparib group vs 15.1 weeks (80% CI = 11.9–22.6 weeks) in the placebo group (adjusted HR = 0.53, 80% CI = 0.30–0.92, P = .07; unadjusted HR = 0.51, 80% CI = 0.31–0.83, P = .04).
KEY POINTS
- Median progression-free survival was 35.3 weeks in the rucaparib group vs 15.1 weeks in the placebo group.
- Median overall survival was not reached vs 72.3 weeks.
Death occurred in 9 patients (45%) in the rucaparib group and 14 patients (70%) in the placebo group. Median overall survival was not reached in the rucaparib group vs 72.3 weeks (80% CI = 51.7–85.4 weeks) in the placebo group (adjusted HR = 1.22, 80% CI = 0.62–2.38, P = .35; unadjusted HR = 0.70, 80% CI = 0.4–1.2, P = .21).
Adverse Events
The safety population included 19 patients in the rucaparib group (1 did not receive treatment because of rapid disease progression) and 20 in the placebo group. Treatment-related adverse events of any grade that were more common in the rucaparib group included fatigue (63% vs 30%), nausea (37% vs 5%), rash (21% vs 0%), and increased alanine aminotransferase (58% vs 10%). Grade ≥ 3 treatment-related adverse events in the rucaparib group consisted of anemia, fatigue, and hypertension in one patient each. Treatment was discontinued because of treatment-related toxicity or patient choice in 26% vs 5% of patients. No treatment-related deaths were observed.
The investigators concluded: “Maintenance rucaparib, following platinum-based chemotherapy, extended progression-free survival in DNA repair deficiency biomarker–selected patients with metastatic urothelial carcinoma and was tolerable. Further investigation of PARP inhibition in selected patients with metastatic urothelial carcinoma is warranted.”
Simon J. Crabb, PhD, MBBS, of Southampton Experimental Cancer Medicine Centre, University of Southampton, is the corresponding author of the Journal of Clinical Oncology article.
Disclosure: The study was funded by Cancer Research UK. Clovis Oncology provided funding to Foundation Medicine for biomarker analysis. For full disclosures of the study authors, visit ascopubs.org.
