Thumbs up for rucaparib maintenance across prognostic subgroups of HRD-negative ovarian cancer

Maintenance with the PARP inhibitor rucaparib after first-line platinum-doublet chemotherapy and cytoreductive surgery appears to reduce the risk of progression in the homologous recombination deficiency (HRD)-negative population of patients with advanced, high-grade ovarian cancer enrolled in the phase III ATHENA-MONO trial, no matter the prognostic factor.

Compared with placebo, rucaparib was associated with a 35-percent reduction in the progression-free survival (PFS) risk (hazard ratio [HR], 0.65, 95 percent confidence interval [CI], 0.45–0.95). The median PFS was 12.1 months with the PARP inhibitor vs 9.1 months with placebo. [ESMO GYN 2025, abstract 75MO]

The PFS benefit with rucaparib was seen across subgroups including those defined by wild-type BRCA and low LOH* tumours, ECOG performance status, FIGO stage at diagnosis, prior use of bevacizumab, timing of cytoreductive surgery, cytoreductive surgery outcome, and radiologic response to chemotherapy, reported presenting study author Dr Vanda Salutari of the Catholic University of the Sacred Heart in Rome, Italy, at the ESMO Gynaecological Cancers annual meeting.

However, the benefit was most notable among patients with measurable disease at baseline (HR, 0.25, 95 percent CI, 0.08–0.80), those with above-normal CA-125 levels at baseline (HR, 0.29, 95 percent CI, 0.10–0.84), and those with residual disease after chemotherapy (HR, 0.38, 95 percent CI, 0.19–0.79), Salutari said.

Previously reported PFS data from ATHENA-MONO favoured rucaparib vs placebo in the HRD-positive population (median PFS, 28.7 vs 11.3 months; HR, 0.47, 95 percent CI, 0.31–0.72; p=0.0004) and in the intention-to-treat population that included patients with HRD-positive and -negative tumours (median PFS, 20.2 vs 9.2 months; HR, 0.52,  95 percent CI, 0.40–0.68; p<0.0001). [J Clin Oncol 2022;40:3952-3964]

Taken together, the ATHENA-MONO data suggest that rucaparib is a potential beneficial therapeutic option for all patients with advanced, high-grade ovarian cancer, including those with HRD-negative tumours, according to Salutari.

HRD-negative population

The phase 3 ATHENA-MONO study included 538 patients with newly diagnosed, stage III–IV, advanced, high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who achieved a complete or partial response following frontline platinum-based chemotherapy. These patients also received cytoreductive surgery that resulted in complete resection. Patients were required to have an ECOG performance status of 0 or 1 and to have no prior frontline maintenance therapy.

Of the patients, 427 were in the rucaparib arm (600 mg) and 111 were in the placebo arm. Treatment was administered orally twice daily and continued for up to 24 months, or until radiographic progression, unacceptable toxicity, or other reasons for discontinuation.

The HRD-negative population comprised 189 patients in the rucaparib arm (median age 64 years, 80.4 percent White) and 49 in the placebo arm (median age 63 years, 81.6 percent White). Most patients in both treatment arms had an ECOG performance status of 0 (67.7 percent and 59.2 percent), had FIGO stage III disease (79.4 percent and 79.6 percent), had no disease burden (75.5 percent and 65.3 percent), had normal CA-125 levels (86.8 percent and 89.8 percent), underwent interval debulking (50.8 percent and 51.0 percent), had a complete R0 resection (63.5 percent and 61.2 percent), had no disease after surgery (54.5 percent and 49.0 percent), and had no residual disease after chemotherapy (75.7 percent and 75.5 percent).

No new safety signals were observed with rucaparib, Salutari noted. Treatment-emergent adverse effects (TEAEs) of any grade occurred in 96.8 percent of patients in the rucaparib arm vs 91.8 percent of those in the placebo arm. The rates of grade ≥3 TEAEs were 58.2 percent and 26.5 percent, respectively.

The most common any-grade TEAEs included asthenia (63.5 percent with rucaparib vs 32.7 percent with placebo), nausea (59.3 percent vs 22.4 percent), anaemia (46.6 percent vs 14.3 percent), and alanine (ALT)/aspartate aminotransferase (AST) level elevation (44.4 percent vs 6.1 percent).

Frequently reported grade ≥3 TEAEs were anaemia (26.5 percent vs 0 percent), neutropenia (14.8 percent vs 0 percent), increased ALT/AST levels (13.2 percent vs 2 percent), thrombocytopenia (7.9 percent vs 0 percent), and asthenia (5.3 percent vs 2.0 percent).