FDA and EU Approval Sought for Rucaparib as Frontline Maintenance in Select Advanced Ovarian Cancer

A supplemental new drug application (sNDA) and a Type II variation has been submitted to the FDA and the European Medicines Agency, respectively, seeking the approval of rucaparib (Rubraca) as frontline maintenance treatment in women with advanced ovarian cancer irrespective of biomarker status who have responded to first-line platinum-based chemotherapy.¹

The submissions were supported by findings from the monotherapy analysis of the phase 3 ATHENA trial (NCT03522246; ATHENA-MONO), in which rucaparib was found to significantly improve progression-free survival (PFS), irrespective of homologous recombination deficiency (HRD) status.²

At a data cutoff date of March 23, 2022, 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); this translated to a 53% reduction in the risk of disease progression or death. 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.

In the intention-to-treat (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), representing a 48% reduction in the risk of disease progression or death. 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.

“We believe the compelling PFS results, the primary end point of the ATHENA-MONO trial, are strongly supportive of an approval and reinforce the potential of [rucaparib] as an important new first-line maintenance treatment for ovarian cancer,” Patrick J. Mahaffy, president and chief executive officer of Clovis Oncology, stated in a 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.”

ATHENA-MONO enrolled patients with newly diagnosed, stage III to IV, high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. To participate, patients were required to have completed first-line platinum doublet chemotherapy and surgery and have achieved a complete response or a partial response per investigator assessment and received cytoreductive surgery. They also needed to have an ECOG performance status of 0 or 1. Patients could not have previously received treatment for ovarian cancer other than a frontline platinum regimen.

Participants were randomly assigned 4:4:1:1 to 1 of 4 arms: arm A received oral rucaparib at a twice-daily dose of 600 mg plus intravenous nivolumab (Opdivo) at 480 mg (n = ~400), arm B received rucaparib at a twice-daily dose of 600 mg plus placebo (n = ~400), arm C received nivolumab at 480 mg plus placebo (n = ~100), and arm D received placebo (n = ~100).

Stratification factors included tumor homologous recombination deficiency test status, disease status following chemotherapy, and timing of surgery.

Treatment was given for 24 months, or until radiographic disease progression, intolerable toxicity, or other discontinuation criteria were met.

ATHENA-MONO only looked at arms B and D. The primary end point for the research was investigator-assessed PFS in those with HRD positivity and in the ITT population. Key secondary end points comprised final overall survival in the HRD population and the ITT population, and objective response rate (ORR) per RECIST criteria in the HRD population and the ITT population.

In the HRD population, the median age in the rucaparib arm was 57 years (range, 30-81) vs 59 years (range, 38-78) in the placebo arm. Most patients in these arms were White (74.1% vs 71.4%, respectively), had an ECOG performance status of 0 (71.4% vs 79.6%), FIGO stage III disease (73.5% vs 63.3%), and epithelial ovarian cancer (82.7% vs 79.6%).

In the rucaparib arm, 56.2% of patients underwent primary surgery and 43.8% had interval debulking; in the placebo arm, these rates were 55.1% and 44.9%, respectively. Most patients in the investigative and control arms did not have residual disease following chemotherapy, at 74.1% and 71.4%, respectively. In the investigative arm, 49.2% of patients had BRCA mutations and 50.8% had BRCA wild-type or high loss of heterozygosity (LOH); these rates were 49.0% and 51.0%, respectively, in the control arm.

In the ITT population, the median age in both the investigative and control arms was 61 years (range, 30-83), and most patients were White (76.8% vs 78.4%, respectively), had an ECOG performance status of 0 (69.1% vs 68.5%), FIGO stage III disease (75.6% vs 70.3%), and epithelial ovarian cancer (78.7% vs 76.6%).

Regarding timing of surgery, 48.9% of those in the rucaparib arm had primary surgery vs 48.6% of those in the placebo arm, and 51.1% vs 51.4%, respectively, had interval debulking. Again, most patients did not have residual disease following chemotherapy (75.4% vs 73.9%, respectively). Among the patients who were HRD positive in the rucaparib arm, 21.3% had BRCA mutations and 22.0% had BRCA wild-type disease or high LOH; in the placebo arm, these rates were 21.6% and 22.5%, respectively.

Additional data showed that among those with BRCA mutations, the median investigator-assessed PFS was not yet reached (NR; 95% CI, 25.8-NR) with rucaparib vs 14.7 months (95% CI, 6.4-NR) with placebo (HR, 0.40; 95% CI, 0.21-0.75). In those with BRCA wild-type disease or high LOH, the median PFS with rucaparib was 20.3 months (95% CI, 13.4-31.1) vs 9.2 months (95% CI, 4.0-22.1) with placebo (HR, 0.58; 95% CI, 0.33-1.01). In those with HRD negativity who received rucaparib or placebo, the median PFS was 12.1 months (95% CI, 11.1-17.7) and 9.1 months (95% CI, 4.0-12.2), respectively (HR, 0.65; 95% CI, 0.45-0.95).

In the HRD-positive population, rucaparib elicited a confirmed ORR of 58.8% (95% CI, 32.9%-81.6%) per RECIST criteria vs 20.0% (95% CI, 0.5%-71.6%) with placebo. The median duration of response (DOR) in the investigative and control arms was 16.7 months (95% CI, 5.7-NR) and 5.5 months (N/A), respectively.

In the ITT population, the confirmed ORRs per RECIST criteria with rucaparib and placebo were 48.8% (95% CI, 32.9%-64.9%) and 9.1% (95% CI, 0.2%-41.3%), respectively. Here, the median DORs were 22.1 months (95% CI, 8.4-NR) and 5.5 months (N/A), respectively.

The safety profile of rucaparib proved to be consistent with what has been observed in prior studies. The most common treatment-emergent adverse effects (TEAEs) that were grade 3 or higher in severity in patients given rucaparib (n = 425) were anemia or decreased hemoglobin (28.7%), decreased neutrophil count or neutropenia (14.6%), increased alanine or aspartate aminotransferase (10.6%), thrombocytopenia or decreased platelet counts (7.1%), asthenia or fatigue (4.9%), and leukopenia or decreased white blood cell counts (3.5%).¹

TEAEs resulted in discontinuation for 11.8% of those who received rucaparib vs 5.5% of those who were given placebo. Three deaths were reported in the investigative arm vs none in the control arm.

References

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. Clovis Oncology, Inc. September 13, 2022. Accessed September 13, 2022. https://bit.ly/3RWqAby
2. 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