sNDA Submitted to the FDA for Rucaparib in Advanced Ovarian Cancer

Data from the monotherapy analysis of the phase 3 ATHENA trial has led to the submission of a supplemental new drug application to the FDA and EMA for rucaparib as treatment for patients with advanced ovarian cancer.

A supplemental new drug application (sNDA) has been submitted to the FDA and EMA for rucaparib (Rubraca) as first-line maintenance treatment for patients with advanced ovarian cancer, regardless of their biomarker status, who have responded to first-line platinum-based chemotherapy, according to a press release from Clovis Oncology, Inc.1

The basis of the sNDA comes from positive data from the monotherapy analysis of the randomized, phase 3 ATHENA trial (GOG-3020/ENGOT-ov45; NCT03522246).

Data demonstrated that rucaparib in the first-line significantly improved investigator-assessed progression-free survival (PFS) when compared with placebo in women with advanced ovarian cancer irrespective of biomarker status in each of the examined populations.

“We believe the compelling PFS results, the primary endpoint of the ATHENA-MONO trial, are strongly supportive of an approval and reinforce the potential of Rubraca as an important new first-line maintenance treatment for ovarian cancer,” said Patrick J. Mahay, president and chief executive office of Clovis Oncology, Inc, in the press release. “We are grateful to the patients who participated in the trial and for the support of the clinical community familiar with these results.”

Rucaparib is an oral, small molecule inhibitor of PARP1, PARP2, and PARP3 currently being developed across multiple tumor types, including ovarian and metastatic castration-resistant prostate cancers, as monotherapy, and in combination with other anticancer agents.

The ATHENA trial was divided into 2 study analyses based on treatment regimens after randomization. Patients were randomized 4:4:1:1 to 1 of 4 treatment arms.2

Patients in arm A were given oral rucaparib at 600 mg twice daily plus intravenous (IV) nivolumab (Opdivo) at 480 mg, arm B was comprised of IV placebo and rucaparib, arm C was made up of oral placebo and nivolumab, and arm D included an IV and oral placebo regimen. Patients were treated for 24 months or until radiographic progression, unacceptable toxicity, or other reasons for discontinuation.

Those enrolled in ATHENA were patients with newly diagnosed stage III to IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer and who completed frontline platinum-doublet chemotherapy. Patients must have achieved investigator-assessed complete response (CR) or partial response (PR), received cytoreductive surgery, had an ECOG performance status of 0 or 1, and had no prior treatments for ovarian cancer.

The primary end point of the trial was PFS by investigator review with secondary end points including blinded independent central review (BICR) PFS, overall survival, objective response rate, duration of response, safety, and tolerability.

For the primary end point, which first evaluated PFS by HRD status in those with BRCA mutant and loss of heterozygosity (LOH)–high, BRCA wild-type disease hierarchical, a step-down design was developed. If the regimen met statistical significance in this group, the study would continue to an ITT analysis. At a 90% power at a 2-sided significance level of 0.025, intended HR values were 0.45 for those with HRD and 0.60 for those in the ITT population.

ATHENA-MONO comprised arms B (n = 400) and D (n = 100), and findings were reported at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting. ATHENA-COMBO included arms A (n = 400) and B (n = 400). The primary end point for the overall trial is investigator-assessed PFS.

Findings presented at ASCO this year from ATHENA-MONO showed that in the HRD group, the investigator-assessed median PFS was 28.7 months (95% CI, 23.0-not reached) vs 11.3 months (95% CI, 9.1-22.1; HR, 0.47; 95% CI, 0.31-0.72; P = .0004). The median PFS by BICR was NR (95% CI, 28.7-NR) vs 9.9 months (95% CI, 6.5-NR; HR, 0.44; 95% CI, 0.28-0.70; P = .0004).3

The intent-to-treat (ITT) population showed a median PFS of 20.2 months (95% CI, 15.2-24.7) in the rucaparib arm vs 9.2 months (95% CI, 8.3-12.2) in the placebo arm (HR, 0.52; 95% CI, 0.40-0.68; log-rank P < .0001). The secondary end point of PFS by BICR showed a median PFS of 25.9 months (95% CI, 16.8- NR) in the rucaparib arm compared with 9.1 months (95% CI, 6.4-9.7) in the placebo arm (HR, 0.47; 95% CI, 0.36-0.63; log-rank P < .0001).

In the investigator-assessed PFS exploratory subgroup analysis, rucaparib continued to demonstrate increased benefit over the placebo, regardless of the presence of a BRCA mutation (HR, 0.40; 95% CI, 0.21-0.75), LOH-high disease (HR, 0.58; 95% CI, 0.33-1.01), or HRD negativity (HR, 0.65; 95% CI, 0.45-0.95). In subgroups evaluated by BICR, the data were similar.

The investigator-assessed objective response rate (ORR) in the HRD population was 58.8% (95% CI, 32.9% vs 81.6%) in the rucaparib arm vs 20.0% (95% CI, 0.5%-71.6%) in the placebo arm, both comprised exclusively of PRs, with median duration of response (DOR) at 16.7 months vs 5.5 months, respectively. In the ITT population, the ORR in the rucaparib arm was 48.8% (95% CI, 32.9%- 64.9%) vs 9.1% (95% CI, 0.2%-41.3%) in the placebo arm, with 1 CR in the rucaparib group. Corresponding median DOR between groups was 22.1 months and 5.5 months.

Regarding safety, at least 1 grade 3 or higher adverse event (AE) was reported for 60.5% of patients given rucaparib vs 22.7% of those given placebo. Treatment interruptions or dose reductions from treatment-emergent AEs (TEAEs) occurred in 63.8% and 21.8% of patients in each arm, respectively.

The most common grade 3 or higher AEs occurring with rucaparib vs placebo included anemia or increased hemoglobin (28.7% vs 0%, respectively), neutropenia or neutrophil count decrease (14.6% vs 0.9%), and increased alanine aminotransferase or aspartate aminotransferase (10.6% vs 0.9%). For those given rucaparib, decrease in thrombocytopenia or platelet count was seen in 7.1% of patients, asthenia/fatigue in 4.9%, and a leukopenia/white blood cell count decrease in 3.5%.

Additionally, patients did not have significant changes in bilirubin or increased levels of drug-induced liver toxicity and through month 12. Seventy-percent of patients continued to receive at least 500 mg of rucaparib twice a day, which was more than 80% of the starting dose.

The discontinuation rate due to treatment emergent AEs was 11.8% for patients treated with rucaparib and 5.5% for those in the placebo arm. There were 3 deaths (0.7%) due to treatment emergent AEs for the rucaparib arm vs 0 in the placebo arm. Further, the median treatment duration for the rucaparib arm was 14.7 months vs 9.9 months for the placebo arm.

Overall, the ATHENA-MONO trial met its primary end point of improved PFS by investigator assessment in both populations given rucaparib vs placebo in the primary efficacy analyses. The safety of rucaparib observed in ATHENA-MONO was consistent with both the current United States and European labels.

1. 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. September 13, 2022. Accessed September 13, 2022.
2. A study in ovarian cancer patients evaluating rucaparib and nivolumab as maintenance treatment following response to front-line platinum-based chemotherapy (ATHENA) Updated November 5, 2021. Accessed September 13, 2022.
3. 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
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