Rucaparib first-line maintenance treatment significantly improves PFS in patients with advanced ovarian cancer
As the optimal first-line maintenance strategy for newly diagnosed advanced ovarian cancer remains unclear, the phase III ATHENA trial sought to assess the PARP inhibitor rucaparib as first-line maintenance treatment in a broad patient population. Rucaparib monotherapy was found to be effective with significant benefit versus placebo in both the intention-to-treat and homologous recombination deficiency (HRD) populations, as well as in the non-nested subgroup of patients without known HRD.
While PARP inhibitors have shown efficacy as first-line maintenance treatment for patients with ovarian cancer, questions remain about the patient population that may benefit from their use. ATHENA was designed to test if rucaparib may be effective as first-line maintenance treatment in a broad patient population, including those without BRCA mutations or other evidence of homologous recombination deficiency (HRD), or high-risk clinical characteristics such as residual disease. At ASCO 2022, results from the ATHENA–MONO comparison of rucaparib vs. placebo were reported.
Patients with newly diagnosed, stage III–IV high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer who had completed cytoreductive surgery (R0 permitted) and 4–8 cycles of first-line platinum-doublet (bevacizumab allowed with chemotherapy) with a response were randomised (4:1) to oral rucaparib 600 mg BID or placebo. Patients were stratified by HRD status (as determined by FoundationOne CDx), residual disease status after chemotherapy, and timing of surgery. The primary endpoint of investigator-assessed PFS per RECIST was assessed in a step-down procedure first in the HRD population (BRCA mutant or BRCA wild-type/loss of heterozygosity [LOH] high carcinoma) and then in the intent-to-treat (ITT) population. Blinded independent central review (BICR)–assessed PFS was a stand-alone, secondary endpoint. PFS in BRCA mutant and HRD-negative patients (BRCA wild-type/LOH low) were exploratory endpoints.
As of March 23, 2022, 427 and 111 patients were randomised to rucaparib monotherapy or placebo. After a median duration of follow-up of 26.1 months, investigator-assessed PFS in the HRD population was significantly longer for rucaparib than for placebo (28.7 vs. 11.3 months, HR[95%CI]: 0.47[0.31-0.72], p= 0.0004), with two-year PFS rates of 56.3% and 35.0%. In the ITT population, a 48% reduction in the risk of disease progression or death was reported. Furthermore, also the BICR-assessed PFS was consistent, statistically significant and clinically relevant in both the HRD and ITT populations. Interestingly, rucaparib demonstrated treatment benefit versus placebo as assessed by the investigator, regardless of BRCA mutation and HRD status (HR 0.40 for BRCAmut, HR 0.58 for BRCAWT/LOHhigh and HR 0.65 for BRCAWT/LOHlow). Data were similar with BICR-assessed PFS for HRD subgroups. Exploratory subgroup analyses revealed that patients at the highest risk have the most benefit from rucaparib. About 10% of the patients had measurable disease at baseline and they continued to respond, both in the HRD and ITT population.
Most common grade ≥3 treatment-emergent adverse events (TEAEs) were anaemia (rucaparib, 28.7% vs. placebo, 0%), neutropenia (14.6% vs. 0.9%), and ALT/AST increased (10.6% vs. 0.9%). There were two deaths due to TEAEs in the rucaparib arm, none in the placebo arm. Rucaparib dose reduction, interruption, and discontinuation due to TEAEs occurred in 49.4%, 60.7%, and 11.8% of patients. The median treatment duration was 14.7 months with rucaparib and 9.9 months with placebo. More than 70% of patients continued to receive at least 500 mg BID rucaparib (>80% of starting dose) through month 12. Finally, changes from baseline in FACT-O TOI scores were similar between rucaparib and placebo in the ITT population.
Rucaparib first-line maintenance treatment significantly improves PFS, irrespective of HRD status. Patients with measurable disease at baseline have further tumour reduction with rucaparib. Rucaparib safety profile is consistent with prior studies and patient-reported outcomes are similar with rucaparib and placebo. To date, overall survival data are still immature.
Monk B, et al. ATHENA–MONO (GOG-3020/ENGOT-ov45): A randomized, double-blind, phase 3 trial evaluating rucaparib monotherapy versus placebo as ovarian cancer maintenance treatment following response to first-line platinum-based chemotherapy in. Presented at ASCO 2022; Abstract LBA5500.