Maintenance rucaparib shows promise in urothelial carcinoma with DNA repair deficiency

Research published in the Journal of Clinical Oncology showed that the PARP inhibitor rucaparib (Rubraca) extended progression-free survival (PFS) when used as switch maintenance following platinum-based chemotherapy in patients with metastatic urothelial carcinoma (mUC) harboring a DNA repair deficiency (DRD).¹

At a median follow-up of 94.6 weeks, the phase 2 trial resulted in a median PFS of 35.3 weeks (80% CI, 11.7-35.6) with rucaparib versus 15.1 weeks (80% CI, 11.9-22.6) with placebo (HR, 0.53; 80% CI, 0.30-0.92; one-sided P = .07). Adverse events (AEs) were mostly low-grade, indicating rucaparib maintenance was tolerable.

Most patients with mUC progress following frontline treatment even if they respond to platinum-based chemotherapy. Maintenance immunotherapy with avelumab (Bavencio) is not effective in all patients, leading to a need for molecularly-targeted maintenance therapy.

The DRD phenotype is believed to predict benefit from cisplatin-based chemotherapy in mUC

and is also associated with mutations in genes including BRCA1, BRCA2, ATM, RB1, PALB2, FANCC, FANCD2, and ERCC2. Based on the known efficacy of PARP inhibitors on these genetic alterations and in mUC cells, rucaparib was investigated as part of the phase 2 ATLANTIS trial platform (ISRCTN25859465).

The phase 2 trial randomly assigned patients with mUC and a DRD biomarker on a 1:1 basis to receive 600 mg of rucaparib or placebo twice a day orally within 10 weeks of completing 4 to 8 cycles of first-line platinum-based chemotherapy. Patients were stratified by cisplatin or non-cisplatin chemotherapy, ECOG performance status, complete or partial response to chemotherapy, and presence of visceral metastases, measurable disease, and investigational site.

Patients were evaluated by imaging of the chest, abdomen, and pelvis at baseline and every 12 weeks in the first year, every 16 weeks in year 2, and every 24 weeks in year 3 and onward until disease progression. The primary end point was investigator-assessed PFS, and secondary end points included overall survival (OS), confirmed response rates, and safety and tolerability.

In total, 248 patients were prescreened for DRD, and 74 were positive for the biomarker. Forty patients were randomly assigned to rucaparib or placebo. At a data cutoff of November 17, 2021, only 3 patients (15%) continued to receive rucaparib and none were receiving placebo.

PFS events occurred in all patients who received placebo and 12 out of 20 (60%) who received rucaparib maintenance. Nine patients (45%) who received rucaparib died versus 14 (70%) who received placebo.

Median OS was not reached in the rucaparib treatment arm, compared with 72.3 weeks (80% CI, 51.7-85.4) for placebo with an adjusted HR of 1.22 (80% CI, 0.62-2.38; P = .35) and an unadjusted hazard ratio of 0.70 (80% CI, 0.4-1.2; P = .21).

Investigators assessed whether DRD status was based on genome-wide loss of heterozygosity (LOH) or germline or somatic alterations such as in BRCA1 and BRCA2. Of the 40 patients evaluated, the DRD biomarker was positive because of high LOH in 22 (55%), a somatic gene alteration in 11 (27.5%), or both in 7 (17.5%). They performed an exploratory analysis of to determine if PFS was associated with the source of DRD positivity and observed a trend toward benefit for rucaparib regardless of LOH status, but not with patients who had LOH but no somatic alteration. They noted that the subgroups were too small to conclude that this was significant.

Patients received a median of 10 cycles, 28 days each, with rucaparib versus 6 cycles with placebo. At least 1 dose reduction was required in 7 (36.8%) patients receiving rucaparib and 4 (20.0%) who received placebo. Five patients who received rucaparib discontinued due to treatment-related toxicity or patient choice.

Lymphopenia and anemia were the most common all-grade AEs in both groups. Fatigue was more common in the rucaparib group in 12 patients (63.2%) versus 6 (30.0%) with placebo, as was increased alanine aminotransferase in 11 patients (57.9%) versus 2 (10%), and nausea in 7 patients (36.9%) versus 2 (5.0%), respectively. Grade 3 or higher anemia, fatigue, and hypertension were each reported in a single patient in the rucaparib group; these were the only grade 3 or higher AEs associated with rucaparib.

Following this trial, 3 patients in the rucaparib group received PD-1–targeted immune checkpoint inhibitor therapy and 1 received paclitaxel. In the placebo group, 11 of 20 (55%) patients received immunotherapy, with 1 also receiving erdafitinib (Balversa) and an experimental agent.

The investigators concluded that rucaparib showed favorable efficacy and tolerability as maintenance. therapy This trial was performed before the approval of avelumab maintenance, so it is unknown how these regimens compare. However, in patients with DRD positivity who are poor candidates for immunotherapy, this option may provide survival benefit, and PARP inhibition could be further investigated in this setting.

Reference

1. 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