Rucaparib Maintenance Elicits Continued PFS Benefit Across Newly Diagnosed Ovarian Cancer Subgroups

Patients with newly diagnosed advanced ovarian cancer who responded to first-line chemotherapy and were then treated with rucaparib (Rubraca) maintenance therapy experienced a sustained and significant improvement in progression-free survival (PFS) irrespective of their risk of progression and exploratory subgroups, according to updated findings from the phase 3 ATHENA-MONO study (NCT03522246) presented at the 2024 ESMO Gynecological Cancers Congress.¹

In the intention-to-treat (ITT) population, treatment with rucaparib elicited a median PFS of 20.2 months (95% CI, 15.6-24.7) vs 9.2 months (95% CI, 8.5-12.2) with placebo (HR, 0.53; 95% CI, 0.41-0.68). Among patients with a homologous recombination deficiency (HRD), the median PFS was 31.4 months (95% CI, 23.0-46.0) in the rucaparib arm and 12.0 months (95% CI, 9.1-22.1) in the placebo arm (HR, 0.49; 95% CI, 0.33-0.73). The median follow-up for PFS was 4.0 years in the rucaparib arm and 3.5 years in the placebo arm.

Further analysis of PFS according to patient subgroups demonstrated benefit with rucaparib among all patients regardless of whether they harbored BRCA mutations, had a high loss of heterozygosity (LOH), or were at a high risk for disease progression. A similar PFS advantage with rucaparib was seen in patients who had a complete response (CR) at baseline. In this population, the median PFS was 15.6 months (95% CI, 10.2-23.0) in the rucaparib arm compared with 6.4 months (95% CI, 2.7-23.0) in the placebo arm (HR, 0.49; 95% CI, 0.24-1.00).

“These data were not shown, but 35% of patients [treated] with rucaparib reached the 2-year treatment cap, with only 17% [of patients] reaching the full 2 years with placebo,” presenting author Rebecca Kristeleit, BSc, MBChB, MRCP, PhD, a consultant medical oncologist and clinical senior lecturer in the Department of Oncology at the University College-London Cancer Institute in England, stated in the presentation. “[Additionally,] after 4 years of follow-up, 29% of rucaparib-treated patients had maintained a CR, compared with 12% of placebo-treated patients,” Kristeleit added.

Previously reported data from the primary analysis of ATHENA-MONO proved the efficacy of rucaparib monotherapy as a first-line maintenance approach in patients with newly diagnosed ovarian cancer with or without HRD. Results showed a median PFS of 28.7 months (95% CI, 23.0-NR) with rucaparib vs 11.3 months (95% CI, 9.1-22.1) with placebo (HR, 0.47; 95% CI, 0.31-0.72; log-rank P = .0004) in the HRD population. The median PFS outcomes in the ITT population were 20.2 (95% CI, 15.2-24.7) months and 9.2 months (95% CI, 8.3-12.2), respectively, (HR, 0.52; 95% CI, 0.40-0.68; log-rank P < .0001).²

The ATHENA trial enrolled patients with newly diagnosed stage III to IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. Eligible patients must have completed frontline platinum-doublet chemotherapy and surgery, achieved either an investigator-assessed CR or partial response, and gone on to receive cytoreductive surgery. An ECOG performance status of 0 or 1 and no prior exposure to frontline maintenance therapy for ovarian cancer were also required.

Patients were randomly assigned 4:4:1:1 to receive 600 mg of oral rucaparib twice daily plus intravenous (IV) nivolumab (Opdivo) at 480 mg (arm A); IV placebo and rucaparib (arm B); oral placebo and nivolumab (arm C); or an IV and oral placebo regimen (arm D).1 Treatment was administered for 24 months or until radiographic progression, unacceptable toxicity, or other reasons for discontinuation. Key stratification factors for randomization included tumor HRD test status, disease status post-chemotherapy, and the timing of surgery.

Following randomization, the ATHENA study was divided into 2 separate analyses according to the treatment regimen administered. ATHENA-MONO comprised arms B (n ≈ 400) and D (n ≈ 100), and the ATHENA-COMBO study included arms A (n ≈ 400) and B (n ≈ 400).

The primary end point of the study was investigator-assessed PFS in the HRD and ITT populations. The data cutoff for the current analysis was March 1st, 2024.

The median PFS in the BRCA-mutant group was NR with rucaparib vs 16.7 months with placebo (HR, 0.47; 95% CI, 0.26-0.84). For patients with BRCA wild-type disease who were LOH high, low, or intermediate, the median PFS with rucaparib was 22.3 months, 12.1 months, and 17.5 months, respectively. Corresponding median PFS outcomes with placebo were 9.2 months (HR, 0.56; 95% CI, 0.33-0.92), 9.1 months (HR, 0.66; 95% CI 0.46-0.96) and 8.9 months (HR, 0.38; 95% CI, 0.19-0.76).

Patients at a high risk for disease progression were classified as FIGO stage IV or FIGO stage III ovarian cancer with residual disease after surgery or prior treatment with neoadjuvant chemotherapy. Patients at a low risk for disease progression were classified as having FIGO stage III ovarian cancer with no residual disease following resection. In the high-risk group, the median PFS was 14.8 months and 9.1 months with rucaparib vs placebo, respectively (HR, 0.47; 95% CI, 0.35-0.63). In the low-risk group, the median PFS in each arm was 31.4 months and 24.0 months (HR, 0.80; 95% CI, 0.49-1.31).

To conclude her presentation, Kristeleit noted that, “the final safety profile was consistent with that of the primary end point analysis, as presented by David M. O’Malley, [MD], of The Ohio State University College of Medicine [in Columbus], at the 2024 ASCO Annual Meeting.”

Disclosures: Dr Kristeleit discloses receiving institutional funding from Clovis Oncology/pharma; grant and research support for the current trial from Incyte; honoraria from AstraZeneca, Basilea, Celcuity, Clovis Oncology/pharma&, Duke Street Bio, Eisai, GSK, iTeos, Leucid, MSD, Prokarium, Seattle Genetics, Shattuck Labs, and Tubulis; and serving on speaker’s bureaus for AstraZeneca, Eisai, GSK, and MSD.

References

1. Kristeleit R, O’Malley D, Lim M, et al. Updated progression-free survival (PFS) in patients (pts) with newly diagnosed advanced ovarian cancer (OC) treated with rucaparib (RUC) in ATHENA-MONO. Ann Oncol. 2024;9(suppl 5):1-19. doi:10.1016/esmoop/esmoop103501
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