ARIEL3

Background

Phase III RCT (ARIEL3). 564 patients with platinum-sensitive recurrent high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer with complete or partial response to most recent platinum-based chemotherapy. Prospectively analyzed in 3 nested biomarker cohorts: BRCA-mutated (n=196), HRd (includes BRCAm, n=354), and overall/intent-to-treat (n=564). Randomized 2:1 to rucaparib 600 mg BID continuous maintenance vs placebo. Rucaparib is an oral PARP1/2 inhibitor.

Interventions and follow up

Arm A: Rucaparib 600 mg BID continuous maintenance until progressio
Arm B: Placebo
Primary endpoint: PFS by investigator assessment in all 3 biomarker cohorts (hierarchically tested)
mFollow up: 19.9 month

Results

Median PFS — BRCAm cohort: 16.6 months (rucaparib) vs 5.4 months (placebo), HR 0.23 (95% CI 0.16–0.34), P<.0001
Median PFS — HRd cohort: 13.6 vs 5.4 months, HR 0.32 (95% CI 0.24–0.42), P<.0001
Median PFS — overall: 10.8 vs 5.4 months, HR 0.36 (95% CI 0.30–0.45), P<.0001

Adverse events

Main adverse events: Grade ≥3 anemia: 18.8%. Grade ≥3 increased ALT/AST: 10.5% / 10.9% — more common with rucaparib than other PARP inhibitors. Grade ≥3 neutropenia: 7.1%. Grade ≥3 thrombocytopenia: 4.1% (lower than niraparib). Nausea grade 1–2: very common (75%). Discontinuation due to AEs: 13% vs 4%. MDS/AML: 0.9% (rucaparib) vs 0.2% (placebo).

Conclusions

Rucaparib maintenance significantly improved PFS across all biomarker groups in platinum-sensitive recurrent ovarian cancer, with greatest benefit in BRCAm (HR 0.23) and meaningful benefit in HRd (HR 0.32) and all-comers (HR 0.36).

Key Limitations

Key Limitations: Liver toxicity (ALT/AST elevations) is more common with rucaparib than olaparib or niraparib, requiring monitoring. Rucaparib's FDA approval was subsequently voluntarily withdrawn (May 2022) for ovarian cancer due to OS findings from ARIEL4 (rucaparib vs chemo in BRCA-mutated relapsed OC) showing inferior OS. The ARIEL3 data remain scientifically valid, but rucaparib is no longer commercially available in the US for ovarian cancer as of 2022.

Clinical Context

ARIEL3 confirmed the broad PARP inhibitor class effect in platinum-sensitive recurrent ovarian cancer. Following the voluntary withdrawal of rucaparib's FDA approval in May 2022 due to ARIEL4 OS findings, olaparib (SOLO2) and niraparib (NOVA) are the current standard maintenance PARP inhibitors for platinum-sensitive recurrent ovarian cancer. The ARIEL4 trial is important: it showed rucaparib treatment had worse OS than chemotherapy in a BRCA-mutated relapsed OC population, demonstrating that PARP inhibitors as active therapy (not maintenance) may be harmful.

References

References: Coleman RL et al, Lancet 2017 (ARIEL3)