PARP Maintenance Extended PFS in Metastatic Urothelial Carcinoma

By Leah Lawrence - August 18, 2022

Maintenance treatment with the PARP inhibitor rucaparib after platinum-based chemotherapy extended progression-free survival in metastatic urothelial carcinoma selected for DNA repair deficiency (DRD).

“Metastatic urothelial carcinoma has a poor prognosis. Development of molecularly targeted treatment options, with predictive biomarkers to aid patient selection, is an important unmet need,” study researchers wrote in The Journal of Clinical Oncology. “PARP inhibitors, including rucaparib, have been extensively investigated and exhibit clinical activity in various platinum-sensitive cancers.”

In this phase 2 study, researchers studied 248 patients with DRD biomarker-positive metastatic urothelial carcinoma who were within 10 weeks of chemotherapy and did not have cancer progression. Of the patients studied, 29.8% were DRD biomarker-positive. These patients were randomly assigned to maintenance rucaparib 600 mg twice a day orally or placebo.

Median progression-free survival was double with rucaparib at 35.3 weeks compared with 15.1 weeks with placebo (hazard ratio [HR]=0.53; 80% CI, 0.30-0.92; one-side P=.07). Median overall survival was not reached in the rucaparib arm and 72.3 weeks in the placebo arm (adjusted HR=1.22; 80% CI, 0.62-2.38; P=.35).

The researchers conducted a subgroup analysis looking at components of the DRD biomarker. They found a trend toward benefit with use of rucaparib in patients with a DRD gene alteration, irrespective of loss of heterozygosity status.

Patients assigned rucaparib received a median of 10 cycles. Treatment-related adverse events were mostly low grade and were more common in patients assigned to rucaparib, according to the researchers. Fatigue (63.2% vs 30.0%), nausea (36.8% vs 5.0%), rash (21.1% vs 0%), and raised alanine aminotransferase (57.9% vs 10%) were all more common in patients assigned rucaparib.

“Further development of PARP inhibition in metastatic urothelial carcinoma is now warranted,” the researchers wrote. “This may require combination strategies and will require further scrutiny of patient genomic phenotypes to optimally integrate into the increasingly complex treatment pathway for this disease.”

Reference

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

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