NICE Approves Maintenance Rucaparib for Relapsed Ovarian Cancer

Meindert Boysen, PharmD

The UK’s National Institute for Health and Care Excellence (NICE) has approved rucaparib (Rubraca) for the maintenance treatment of patients with relapsed ovarian, fallopian tube, or peritoneal cancer that has responded to platinum-based chemotherapy.¹

The decision is based on data from the phase III ARIEL3 trial, in which rucaparib led to a median progression-free survival (PFS) of 10.8 months compared with 5.4 months in patients who received placebo, translating to a 68% reduction in the risk of disease progression or death (HR, 0.32; 95% CI, 0.24-0.42]; P <.0001).² 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).

“Many people with advanced ovarian cancer experience recurrent disease which requires multiple rounds of chemotherapy. Rucaparib offers patients a new treatment option to help prevent cancer growth, delaying the need for further chemotherapy and the associated side effects,” Meindert Boysen, PharmD, director of the NICE Centre for Health Technology Evaluation, said in a press release.

“We’re therefore pleased with the positive response from the company that has led to rucaparib being approved for use in the Cancer Drugs Fund. This will allow patients to access the treatment immediately, while more evidence can be collected on its overall survival benefit,” added Boysen.

The approval will allow approximately 1350 patients in England to receive the PARP inhibitor, which would be made immediately available through the committee’s Cancer Drugs Fund (CDF).

The decision differs from the committee’s prior opinion on rucaparib. In a July 2019 statement, NICE explained that that due to the immature overall survival (OS) data and the cost-effectiveness estimates being higher than what NICE normally considers acceptable, it did not recommend the PARP inhibitor for routine use in the National Health Service.³

However, NICE announced in the press release that Clovis Oncology, the developer of rucaparib, has since proposed an alternative price for the PARP inhibitor. The committee added that if the revised commercial arrangement is supported with long-term OS data, rucaparib could be a potential cost-effective method of NHS resources. Due to this, NICE therefore decided to include rucaparib in the CDF in order for the long-term data to be collected.

In the ARIEL3 trial, patients with platinum-sensitive, high-grade ovarian, fallopian tube, or primary peritoneal cancer were randomized 2:1 to receive rucaparib (n = 375) or placebo (n = 189). The 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 homologous recombination deficiency (HRD)—positive, which could include BRCA-mutant or wild-type with a high loss of heterozygosity (LOH; n = 354). A third group assessed all-comers in the intent-to-treat (ITT) 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). Rucaparib was administered orally at 600 mg twice daily. In the BRCA-mutant group, 130 patients received rucaparib and 66 patients had placebo. In the HRD group, 236 got rucaparib and 118 received placebo. The ITT group contained those with BRCA-mutant and wild-type tumors and those with high, indeterminate, and low genomic LOH.

Additional data showed that the overall response rate (ORR) with rucaparib was 18%, which comprised 10 complete responses (CRs) versus 8% ORR and 1 CR with placebo. The key secondary endpoint of extending PFS by independent radiological review versus placebo in the ITT population, regardless of BRCA status, was a median 13.7 months versus 5.4 months with rucaparib and placebo, respectively.

In patients with germline or somatic BRCA mutations, the median PFS with rucaparib was 16.6 months (95% CI, 13.4-22.9) versus 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 HRD or low to high loss of 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 ORR was 38% for rucaparib versus 9% with placebo. There were 7 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.

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).

Regarding safety, 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.

“Inclusion of rucaparib in the CDF as an option for maintenance treatment for patients with recurrent ovarian cancer responding to platinum-based therapy regardless of BRCA mutation status or line of treatment in the relapsed maintenance setting represents a much-needed treatment option for women with recurrent ovarian cancer,” Jonathan Ledermann, MD, professor of Medical Oncology, UCL Cancer Institute and UCL Hospitals, London, global principal investigator for non-US sites in the ARIEL3 study, said in a separate press release.⁴

“I am pleased that the CDF recommendation includes access for the broad patient population evaluated in the ARIEL3 trial which demonstrated rucaparib to be effective in eligible patients, regardless of their BRCA mutation status, providing a clinically-meaningful median progression-free survival of more than one year across the entire population studied by independent radiological review. This represents a significant step in the effective management of relapsed ovarian cancer in the NHS in England,” added Ledermann.

In April 2018, the FDA approved rucaparib tablets for use as a maintenance treatment for patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.

References

1. Another Treatment Option for Ovarian Cancer Approved for the Cancer Drugs Fund. National Institute for Clinical Excellence. Published October 11, 2019. https://bit.ly/2MsIiDC. Accessed October 11, 2019.
2. Ledermann J, Oza AM, Lorusso D, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;390(10106):1949-1961. doi: 10.1016/S0140-6736(17)32440-6.
3. Rucaparib for Maintenance Treatment of Relapsed Platinum-Sensitive Ovarian, Fallopian Tube or Peritoneal Cancer That Has Responded to Platinum-Based Chemotherapy [Appraisal Document]. National Institute for Clinical Excellence. July 2019. https://bit.ly/2B48mje.
4. Clovis Oncology Announces Rubraca (rucaparib) Now Available for Women with Relapsed Ovarian Cancer in England Through the Cancer Drugs Fund. Clovis Oncology, Inc. Published October 11, 2019. https://bwnews.pr/2OFH2Qq. Accessed October 11, 2019.