sNDA Submitted to FDA for Maintenance Rucaparib Approval in Ovarian Cancer

Patrick J. Mahaffy, president and CEO of Clovis Oncology

Patrick J. Mahaffy

Based on findings from the phase III ARIEL3 trial, a supplemental new drug application (sNDA) has been submitted to the FDA for rucaparib (Rubraca) as maintenance therapy for patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy, according to Clovis Oncology, the manufacturer of the PARP inhibitor.

Findings from the trial demonstrated maintenance rucaparib improved median progression-free survival (PFS) by 11.2 months compared with placebo for patients with BRCA-mutant platinum-sensitive ovarian cancer.

For patients with germline or somatic BRCA mutations, there was a 77% reduction in the risk of progression or death with rucaparib versus placebo (HR, 0.23; 95% CI, 0.16-0.34;P<.0001). Moreover, the median PFS with rucaparib was 16.6 months (95% CI, 13.4-22.9) compared with 5.4 months for placebo (95% CI, 3.4-6.7). Similar PFS benefits were observed in patients with BRCA wild-type tumors and those with homologous recombination deficiency (HRD) or low to high loss of heterozygosity (LOH).

&ldquo;The submission of the sNDA for rucaparib in the ovarian cancer maintenance setting just 4 months after we reported topline results marks an important milestone that brings Clovis closer to our ultimate goal of making rucaparib available to a broader population of women with advanced ovarian cancer,&rdquo; Patrick J. Mahaffy, president and CEO of Clovis Oncology, said in a statement. &ldquo;We believe that the ARIEL3 results demonstrate the potential of rucaparib to provide a new, much-needed therapeutic option for women with advanced ovarian cancer.&rdquo;

In the ARIEL3 trial, patients with platinum-sensitive, high-grade ovarian, fallopian tube, or primary peritoneal cancer were randomized in a 2:1 ratio to receive rucaparib or placebo. Endpoints were prospectively assessed across 3 cohorts. In the first, patients had BRCA-positive tumors, including both germline and somatic alterations (n = 196). In the second group, patients were HRD-positive, which could include BRCA-mutant or wild-type with a high LOH (n = 354). A third group assessed all-comers in the intent-to-treat population (n = 564).

All enrolled patients had received &ge;2 prior platinum-based therapies, and continued to have platinum-sensitive ovarian cancer (defined as progression in &ge;6 months on their last platinum-based therapy). Oral rucaparib was administered at 600 mg twice daily. In the BRCA-mutant group, 130 patients received rucaparib and 66 got placebo. In the HRD group, 236 got rucaparib and 118 received placebo. The intent-to-treat group contained those with BRCA-mutant and wild-type tumors and those with high, indeterminate, and low genomic LOH.

In theBRCA-mutant group, by blinded independent central review (BICR), which was a secondary endpoint, the median PFS with rucaparib was 26.8 months compared with 5.4 months for placebo (HR, 0.20; P <.0001). The objective response rate (ORR) was 38% for rucaparib versus 9% with placebo. There were 7 complete responses (CR) with the PARP inhibitor and none for placebo.

In the HRD group, the investigator assessed PFS was 13.6 versus 5.4 months for rucaparib and placebo, respectively (HR, 0.32;P<.0001). In the BICR assessment, the median PFS was 22.9 months with the PARP inhibitor versus 5.5 months with placebo (HR, 0.34;P<.0001). The ORRs were 27% (10 CRs) and 12% (0 CRs) for rucaparib and placebo, respectively.

In the intent-to-treat group, for rucaparib and placebo, respectively, the PFS was 10.8 versus 5.4 months by investigator assessment (HR, 0.36;P<.0001) and 13.7 versus 5.4 months by BICR (HR, 0.35;P<.0001). The ORR with rucaparib was 18% (10 CRs) versus 8% with placebo (1 CR).

An exploratory analysis looked at outcomes specifically in those with BRCA wild-type tumors with LOH high (n = 158) and low status (n = 161). In the LOH high group, the median PFS was 9.7 months with rucaparib versus 5.4 months with placebo (HR, 0.44;P<.0001). In the LOH low group, the medians were 6.7 and 5.4 months for rucaparib and placebo, respectively (HR, 0.58;P= .0049). By BICR, for rucaparib and placebo, respectively, the medians were 11.1 versus 5.6 months for the LOH high group (HR, 0.55;P= .0135) and 8.2 versus 5.3 months for the LOH low group (HR, 0.47;P= .0003).

The most common grade &ge;3 treatment-emergent adverse events (TEAEs) with rucaparib were anemia/decreased hemoglobin (19%), increase in ALT/AST (10%), neutropenia (7%), asthenia/fatigue (7%), thrombocytopenia (5%), vomiting (4%), and nausea (4%). TEAEs led to treatment discontinuation for 13.4% of patients in the rucaparib arm versus 1.6% for placebo. Three patients developed treatment-emergent myelodysplastic syndrome/acute myeloid leukemia with rucaparib versus none for placebo.

Rucaparib was initially approved by the FDA in December 2016 as a monotherapy for patients with ovarian cancer with a deleterious BRCA mutation following prior treatment with 2 or more chemotherapies.

Reference:

Ledermann J, Oza AM, Lorusso D, et al. ARIEL3: A Phase 3, Randomised, Double-Blind Study of Rucaparib vs Placebo Following Response to Platinum-Based Chemotherapy for Recurrent Ovarian Carcinoma (OC). Presented at: 2017 ESMO Congress; September 8-12; Madrid, Spain. Abstract Abstract LBA40_PR.