Rucaparib maintenance therapy extends PFS in platinum-responsive metastatic urothelial carcinoma

Results from the ATLANTIS trial platform indicated 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].

The ATLANTIS trial (ISRCTN25859465) evaluated maintenance therapy with rucaparib following platinum-based chemotherapy in patients who have metastatic urothelial carcinoma harbouring 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 randomised 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, 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 1 participant given rucaparib, suggesting that the longer duration of PFS with rucaparib might 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.”

1. Robertson AG, et al. Cell. 2017;171:540–556.


2. Rimar KJ, et al. Cancer. 2017;123:1912–1924.


3. Coleman RL, et al. Lancet. 2017;390:1949–1961.


4. Fulton B, et al. Trials 2020;21:344.


5. 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, 17–19 February.

 

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Posted on 8 April, 20228 April, 2022