EU Panel Recommends Rucaparib for Frontline Maintenance in Advanced Ovarian Cancer

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion regarding the approval of a Type II variation application for rucaparib (Rubraca) as a frontline maintenance treatment in patients with advanced ovarian cancer who have responded to first-line, platinum-based chemotherapy, irrespective of BRCA mutational status.¹

The recommendation is supported by data from the phase 3 ATHENA-MONO trial (GOG-3020/ENGOT-ov45; NCT03522246) in which rucaparib maintenance (n = 185) improved median progression-free survival (PFS) vs placebo (n = 49), at 28.7 months (95% CI, 23.0-not reached [NR]) vs 11.3 months (95% CI, 9.1-22.1), translating to a reduction in the risk of disease progression or death of 53% in the homologous recombination–deficient (HRD) population (HR, 0.47; 95% CI, 0.31-0.72; P = .0004).²

This was also true in the intention-to-treat (ITT) population, where rucaparib (n = 427) resulted in a median PFS of 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) and in the HRD-negative population, at a median of 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).

“We are delighted that CHMP has adopted a positive opinion, recommending rucaparib as a first-line maintenance treatment in patients with advanced ovarian cancer who have responded to first-line platinum-based treatment,” Frank Rotmann, founder and managing director of pharma&, stated in a press release.¹ “Today’s positive opinion is a significant milestone in pharma&’s commitment to ensuring enduring availability to essential medicines like rucaparib, allowing healthcare providers and patients access to the treatments they rely on.”

The randomized, double-blind, placebo-controlled, phase 3 ATHENA-MONO trial enrolled patients with newly diagnosed, stage III to IV, high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer.³ They must have completed first-line treatment with platinum-doublet chemotherapy and achieved a complete or partial response by investigator assessment. They also must have received primary or interval cytoreductive surgery. They also needed to have an ECOG performance status of 0 or 1. They could not have previously received treatment for their disease beyond platinum-based chemotherapy.

Study participants were randomized 4:4:1:1 to receive rucaparib at 600 mg twice daily plus nivolumab (Opdivo) at 480 mg (arm A), rucaparib at 600 mg twice daily plus placebo (arm B), placebo plus nivolumab at 480 mg (arm C), or placebo plus placebo (arm D). Treatment continued for 24 months or until patients experienced radiographic progression, intolerable toxicity, or met other discontinuation criteria.

Key stratification factors included HRD status, disease status following chemotherapy, and timing of surgery.

For the ATHENA-MONO analysis, arm B was compared with arm D. The analysis utilized a hierarchical step-down design where investigator-assessed PFS was evaluated first in the HRD population comprised of those with BRCA mutations and those with BRCA wild-type and high loss of heterozygosity (LOH). Investigator-assessed PFS was then examined in the ITT population.

Important secondary end points included final overall survival in the HRD population and then in the ITT population. This was followed by an evaluation of objective response rates (ORRs) by RECIST v1.1 criteria in the HRD population, followed by the ITT population. Blinded independent central review (BICR)–assessed PFS represents a standalone secondary efficacy end point outside of the step-down analysis.

In the HRD population, the median age across the rucaparib and placebo arms was 58 years (range, 30-81). Most patients were White (74.1% vs 71.4%), had an ECOG performance status of 0 (71.4% vs 79.6%), had stage III disease by International Federation of Gynecology and Obstetrics criteria (73.5% vs 63.3%), and epithelial ovarian cancer (82.7% vs 79.6%).

Moreover, approximately half of patients had primary surgery (56.2% vs 55.1%) and the remainder had interval debulking surgery (43.8% vs 44.9%). Most patients did not have residual disease after chemotherapy (74.1% vs 71.4%). In those who were HRD positive, 49.2% of those in the rucaparib arm and 49.0% of those in the placebo arm had BRCA mutations; 50.8% vs 51.0% of patients, respectively, had BRCA wild-type and high LOH. Additionally, 9.2% of those in the rucaparib arm vs 10.2% of those in the placebo arm had measurable disease at baseline.

BICR-assessed PFS proved to be similar across the HRD subgroups. The hazard ratio (HR) for PFS in the BRCA-mutated population was 0.48 (95% CI, 0.23-1.00); it was 0.46 (95% CI, 0.26-0.81) in the BRCA wild-type/LOH-high group and 0.60 (95% CI, 0.40-0.89) in the HRD-negative group.

Additionally, in the HRD population, the confirmed ORR achieved with rucaparib was 58.8% (95% CI, 32.9%-81.6%) vs 20.0% (95% CI, 0.5%-71.6%) with placebo; the median duration of response (DOR) was 16.7 months (95% CI, 5.7-NR) vs 5.5 months, respectively. In the ITT population, the ORRs achieved with rucaparib and placebo were 48.8% (95% CI, 32.9%-64.9%) and 9.1% (95% CI, 0.2%-41.3%), respectively; the median DOR was 22.1 months (95% CI, 8.4-NR) and 5.5 months, respectively.

Regarding safety, 96.7% of those in the rucaparib arm (n = 425) and 92.7% of those in the placebo arm (n = 110) experienced at least 1 any-grade treatment-emergent adverse effect (TEAE); these effects were grade 3 or higher in 60.5% and 22.7% of patients, respectively. Dose interruptions or reductions were required in 63.8% of those in the rucaparib arm vs 21.8% of those in the placebo arm; 11.8% vs 5.5% of patients, respectively, discontinued treatment because of TEAEs. Two patients in the rucaparib arm died.

The most common TEAEs experienced by those in the rucaparib arm included nausea (any grade, 56.2%; grade ≥3, 1.9%), asthenia (55.8%; 4.9%), anemia (46.6%; 28.7%), increased alanine or aspartate aminotransferase (42.6%; 10.6%), decreased neutrophil count or neutropenia (27.8%; 14.6%), abdominal pain (24.9%; 0.5%), diarrhea (24.0%; 1.4%), thrombocytopenia or decreased platelet count (23.8%; 7.1%), vomiting (23.5%; 1.4%), dysgeusia (21.2%; 0.2%), arthralgia (20.2%; 0.2%), headache (20.0%; 0.5%), constipation (19.3%; 0%), reduced appetite (17.9%; 0.5%), and pruritus (16.2%; 0.2%).

“In the ATHENA-MONO trial, rucaparib prolonged progression-free survival, irrespective of molecular characteristics, and its potential approval by the European Medicines Agency as a first-line maintenance treatment is an important step forward in this difficult-to-treat population,” Rebecca Kristeleit, BSc, MBChB, MRCP, PhD, consultant medical oncologist and adjunct reader at Guy’s and St. Thomas’ NHS Foundation Trust and King’s College London, in London, United Kingdom, and European Network of Gynaecological Oncological Trial lead of the ATHENA trial, added in the press release.¹ “Women with advanced ovarian cancer need and deserve new treatment options to improve outcomes, and today’s recommendation is hopeful news for eligible patients in Europe.”

The European Commission will review the recommendation and issue a decision on the application in the coming months.

References

1. pharmaand GmbH receives positive CHMP opinion for Rubraca (rucaparib) as a first-line maintenance treatment in advanced ovarian cancer. News release. pharmaand GmbH. October 16, 2023. Accessed October 17, 2023. https://live-pharmaandcorp.pantheonsite.io/wp-content/uploads/2023/10/PM15-08.23-pharma-rucaparib-1st-line-maint-CHMP-News-Release-FINAL-Oct-2023.pdf
2. Monk BJ, Parkinson C, Lim MC, et al. A randomized, phase III trial to evaluate rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer (ATHENA-MONO)/GOG-3020/ENGOT-ov45. J Clin Oncol. 2022;40(34):3952-3964. doi:10.1200/JCO.22.01003
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