The final analysis of the phase 3 ARIEL4 trial has revealed challenging results for rucaparib in treating relapsed BRCA-mutated ovarian carcinoma, raising important questions about treatment sequencing in this patient population.
At a median follow-up of 41.2 months, patients treated with rucaparib showed a median overall survival (OS) of 19.4 months compared to 25.4 months in the chemotherapy group (HR, 1.3; 95% CI, 1.0-1.7; P = .0472). The trial's mortality rate reached 70%, with 72% of deaths in the rucaparib arm and 66% in the chemotherapy arm.
Subgroup Analysis Shows Variable Outcomes
The impact on platinum-resistant disease patients was particularly notable, with rucaparib showing significantly shorter survival (14.2 months) compared to chemotherapy (22.2 months). However, in platinum-sensitive subgroups, the outcomes were more comparable between treatments, with combined platinum-sensitive patients showing median OS of 29.4 months with rucaparib versus 27.6 months with chemotherapy.
Trial Design and Patient Population
The study enrolled 349 patients, randomized 2:1 to receive either rucaparib (600 mg twice daily) or standard chemotherapy. Eligible participants were women aged 18 or older with confirmed high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer carrying BRCA1 or BRCA2 mutations. All patients had received at least two prior therapies, including one platinum-based regimen.
Safety Profile Considerations
Treatment-emergent adverse events were significant in both arms, with some notable differences:
- Rucaparib group showed higher rates of liver enzyme elevation (57% vs 19%)
- Anemia was more common with rucaparib (23% vs 6% grade 3)
- Neutropenia was more frequent in the chemotherapy arm (14% vs 7% grade 3)
Ten deaths in the rucaparib group and one in the chemotherapy group were attributed to treatment-emergent adverse events.
Clinical Implications
Dr. Amit M Oza, lead study author from Princess Margaret Cancer Centre, emphasized that these results highlight the need for better understanding of appropriate treatment sequences, particularly following PARP inhibitor progression. This becomes especially relevant given the 2022 restriction of PARP inhibitor indications to maintenance therapy only.
The findings suggest that careful consideration is needed when selecting treatment options for BRCA-mutated ovarian cancer patients, particularly those with platinum-resistant disease. The results also underscore the importance of developing more effective strategies for patients who progress on PARP inhibitors.
