Maintenance Rucaparib Highly Effective Across Ovarian Cancer Subtypes

Jonathan Ledermann, MD

Maintenance treatment with the PARP inhibitor rucaparib (Rubraca) improved median progression-free survival (PFS) by 11.2 months compared with placebo for patients with BRCA-mutant platinum-sensitive ovarian cancer, according to findings from the phase III ARIEL3 trial presented at the 2017 ESMO Congress.

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).

“The improvement in progression-free survival was greatest in the BRCA-mutated group, who had a 77% increase, but it was seen across three subgroups that were evaluated,” lead investigator Jonathan Ledermann, MD, professor of Medical Oncology, UCL Cancer Institute, London, UK, said in a statement. “These results reinforce rucaparib’s potential to provide an enduring and significant clinical benefit in women with advanced ovarian cancer, regardless of their tumor genetics.”

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 ≥2 prior platinum-based therapies, and continued to have platinum-sensitive ovarian cancer (defined as progression in ≥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 the BRCA-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 ≥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.

“It is both impressive and encouraging that rucaparib demonstrated improvements in key primary, secondary, and exploratory endpoints in all 3 ARIEL3 patient populations," said Ledermann. "It is also clinically significant that rucaparib not only sustained patients’ most recent response to platinum, but in some trial participants also enhanced that response, including the radiological elimination of residual tumor.”

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. Based on findings from the ARIEL3 trial, Clovis Oncology, the company developing the drug, plans to submit a supplemental new drug application to the FDA for an expanded approval. This submission is planned for October 2017, according to the company.

“ARIEL3 achieved a huge decrease in the risk of relapse with rucaparib. All of the patient subgroups benefitted, especially those with BRCA mutations but also HRD patients," said ESMO spokesperson Andrés Poveda, MD, head of the Gynaecological Cancer Clinic, Oncology Foundation Institute Valencia, Spain. “Personalized medicine has arrived in high grade serious ovarian cancer. Further studies are needed to identify predictive biomarkers of response to PARP inhibitors. Specifically, we need to know whether there are non-HRD factors that predict response.”

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.

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“We had hoped that the LOH test would distinguish responders from non-responders but both high and low LOH groups benefitted," said Ledermann. "However, the magnitude of progression-free survival benefit was greater in the BRCA wild type/LOH high patients.”