Results from the ATLANTIS trial platform indicate that rucaparib could play a role in the maintenance treatment of metastatic urothelial carcinoma with a DNA repair deficiency that has responded to first-line platinum-based chemotherapy.
A substantial subset of metastatic urothelial carcinomas exhibits a DNA repair deficiency (DRD) phenotype which may predict benefit from platinum-based chemotherapy and sensitivity to PARP inhibition [1,2]. Rucaparib is a potent PARP inhibitor, approved as monotherapy for maintenance treatment of relapsed high-graded epithelial ovarian, fallopian tube, or primary peritoneal cancer following platinum-based chemotherapy [3]. Maintenance therapy with rucaparib following platinum-based chemotherapy was evaluated in the ATLANTIS trial (ISRCTN25859465), in patients who have metastatic urothelial carcinoma harboring a DRD biomarker and who have derived clinical benefit from platinum-based chemotherapy.
ATLANTIS is an adaptive, multi-comparison, phase 2 trial platform [4]. It tests multiple biomarker-selected maintenance therapies for metastatic urothelial carcinoma after 4–8 platinum-based chemotherapy cycles without disease progression. Allocation to the rucaparib comparison was based on ≥10% genomic loss of heterozygosity (%LOH) and/or somatic alteration in defined DRD-associated genes and/or germline BRCA1/2 alteration. Biomarker-positive patients were randomized to maintenance rucaparib (n=20) or matched placebo (n=20) within 10 weeks of completing platinum-based chemotherapy, until disease progression. The primary endpoint was progression-free survival (PFS). Dr. Simon Crabb (University of Southampton, UK) presented the final analysis of the rucaparib arm in the ATLANTIS trial [5].
At a median follow-up of 94.6 weeks, a total of 12 (60%) and 20 (100%) PFS events occurred in the rucaparib and placebo arms respectively. Median PFS was 35.3 weeks with rucaparib and 15.1 weeks with placebo (HR 0.53; P=0.07). A partial response was reported for one participant given rucaparib, suggesting that the longer duration of PFS with rucaparib appears to have been primarily because of maintenance of a pre-existing response to prior chemotherapy rather than producing new objective responses during maintenance treatment. Treatment-related adverse events were mostly low grade. Rucaparib was tolerable with a median duration of 10 rucaparib or 6 placebo cycles on treatment. The most frequent treatment-related adverse events were more common with rucaparib and included fatigue (63.2% vs 30.0%), nausea (36.9% vs 5.0%), and rash (21.1% vs 0%). “These results show that maintenance rucaparib, following platinum-based chemotherapy, extended PFS in DRD biomarker-selected patients with metastatic urothelial carcinoma and is tolerable,” concluded Dr. Crabb. “Further investigation of PARP inhibition for this indication is warranted.”
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- Crabb SJ., et al. A randomized, double-blind, biomarker selected, phase II clinical trial of maintenance PARP inhibition following chemotherapy for metastatic urothelial carcinoma (mUC): Final analysis of the ATLANTIS rucaparib arm. Abstract 436, ASCO GU 2022 Virtual Meeting, 17–19 February.
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