FDA Seeks to Restrict Rucaparib to Second-line Maintenance Therapy in Recurrent Ovarian Cancer

FDA

The FDA has asked Clovis Oncology to limit use of rucaparib (Rubraca) to second-line maintenance therapy for patients with recurrent ovarian cancer harboring BRCA mutations.¹

The company is considering the FDA’s request. If the 2 sides cannot reach an agreement on the revised indication, the FDA said would convene an Oncologic Drugs Committee meeting to review the matter. Clovis warned investors in a 10-Q filing on November 9 that bankruptcy is increasingly likely “in the very near term,” due in part to the “uncertain market potential” of rucaparib.²

On November 16, the company filed an 8-K form with the Securities and Exchange Commission referring to a November 14 meeting with FDA representatives. The 2 sides met to discuss overall survival (OS) data from the phase 3 ARIEL3 trial (NCT01968213), which formed the basis for the April 2018 FDA approval of rucaparib as second-line maintenance treatment in adults with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.³

In ARIEL3 (N = 561), rucaparib demonstrated a statistically significant improvement in estimated median progression-free survival (PFS) compared with placebo (10.8 vs. 5.4 months; HR 0.36; 95% CI, 0.30-0.45).

Clovis submitted final OS data, including in exploratory subgroups, from the ARIEL3 study to the FDA in September 2022. In findings presented at the International Gynecologic Cancer Society 2022 Annual Global Meeting, the median OS was 45.9 months (95% CI, 37.7-43.2-59.6) in the patients in the BRCA-mutant cohort who received rucaparib vs 47.8 months (95% CI, 43.2-55.8) among patients who received placebo (HR, 0.832; 95% CI, 0.581-1.192).⁴

Among those with homologous recombination deficiency (HRD)­, rucaparib induced a median OS of 40.5 months (95% CI, 36.6-48.4) compared with 47.8 months (95% CI, 42.7-53.0) for those who received placebo (HR, 1.005; 95% CI, 0.766-1.320). In the intention-to-treat (ITT) population, the median OS was 36.0 vs 43.2 months in favor of placebo (HR, 0.995; 95%, CI, 0.809-1.223).

In post-progression outcomes (PFS2), rucaparib induced a median of 26.1 months (95% CI, 22.8-32.8) compared with 18.4 months (95% CI, 15.7-24.4) for those who received placebo (HR, 0.672; 95% CI, 0.480-0.941). In the ITT population, the median PFS2 was 20.0 vs 16.3 months in favor of placebo (HR, 0.703; 95%, CI, 0.579-0.854). In the HRD cohort, the median PFS2 was 24.7 vs 18.4 months in favor of placebo (HR, 0.718; 95%, CI, 0.558-0.923).

Investigators noted that rucaparib did not improve OS. However, they pointed out that the PARP inhibitor maintained a progression-free survival (PFS)benefit through subsequent therapy as a maintenance therapy for recurrent, platinum-sensitive ovarian carcinoma.

In June 2022, Clovis voluntarily withdrew the indication of rucaparib for BRCA-mutated ovarian cancer following at least 2 prior chemotherapies in the United States and Europe. The FDA granted accelerated approval to the PARP inhibitor in December 2016 for the treatment of patients with deleterious BRCA mutation (germline and/or somatic)–associated advanced ovarian cancer following 2 or more chemotherapies. In 2 open-label, single-arm trials, investigator-assessed ORR was 54% with a median duration of response of 9.2 months.⁵

In September 2022, Clovis filed supplemental new drug application with the FDA and a Type II variation with the European Medicines Agency, seeking approval of rucaparib as frontline maintenance treatment in women with advanced ovarian cancer irrespective of biomarker status who have responded to first-line platinum-based chemotherapy.⁶

Findings from the phase 3 ATHENA trial (NCT03522246; ATHENA-MONO) showed that the investigator-assessed PFS in patients who were HRD-positive and received rucaparib (n = 185) was 28.7 months (95% CI, 23.0–not reached) vs 11.3 months (95% CI, 9.1-22.1) with placebo (n = 49; HR, 0.47; 95% CI, 0.31-0.72; P = .0004). The 12-month PFS rates in the investigative and control arms were 72.8% and 47.7%, respectively; at 24 months, these rates were 56.3% and 35.0%, respectively.⁷

In the ITT population, the median investigator-assessed PFS with rucaparib (n = 427) was 20.2 months (95% CI, 15.2-24.7) vs 9.2 months (95% CI, 8.3-12.2) with placebo (n = 111; HR, 0.52; 95% CI, 0.40-0.68; P < .0001). The 12-month PFS rates were 63.0% and 42.1%, respectively; the 24-month PFS rates in this population were 45.1% and 25.4%, respectively.

References

1. US Securities and Exchange Commission. Form 8-K. November 14, 2022. Accessed November 18, 2022. https://bit.ly/3TN9JbV
2. US Securities and Exchange Commission. Form 10-Q. November 9, 2022. Accessed November 18, 2022. https://bit.ly/3GpeqFO
3. FDA approves rucaparib for maintenance treatment of recurrent ovarian, fallopian tube, or primary peritoneal cancer. April 6, 2018. Accessed November 18, 2022. https://bit.ly/3XilHNx
4. Coleman RL, Oza AM, Lorusso D, et al. Overall survival results from ARIEL3: a phase 3 randomized, double-blind study of rucaparib vs placebo following response to platinum-based chemotherapy for recurrent ovarian carcinoma. IGCS 2022 Annual Global Meeting; September 29-October 1, 2022; New York, New York.
5. Balasubramaniam S, Beaver JA, Horton S, et al. FDA approval summary: rucaparib for the treatment of patients with deleterious BRCA mutation-associated advanced ovarian cancer. Clin Cancer Res. 2017;23(23):7165-7170. doi:10.1158/1078-0432.CCR-17-1337
6. Clovis Oncology submits applications for Rubraca label expansion in the US and European Union as first-line maintenance treatment in women with advanced ovarian cancer. News release. Clovis Oncology, Inc. September 13, 2022. Accessed November 18, 2022. https://bit.ly/3RWqAby
7. Monk BJ, Parkinson C, Lim MC, et al. ATHENA-MONO (GOG-3020/ENGOT-ov45): a randomized, double-blind, phase 3 trial evaluating rucaparib monotherapy versus placebo as maintenance treatment following response to first-line platinum-based chemotherapy in ovarian cancer. J Clin Oncol. 2022;40(suppl 17):LBA5500. doi:10.1200/JCO.2022.40.17_suppl.LBA5500