Rucaparib delayed disease recurrence in the intent to treat population and across subgroups of women with ovarian cancer.
Jonathan Ledermann MD, FRCP
Rucaparib (Rubraca) delayed disease recurrence in the intent to treat (ITT) population and across subgroups of women with ovarian cancer, according to findings presented at the 2017 international meeting of the European Society of Gynaecological Oncology (ESGO 20).
Investigator-assessed median progression-free survival (PFS) in the ITT population (N = 564) favored rucaparib, 10.8 months versus 5.4 months (hazard ratio [HR], 0.36; P<.0001). Compared with those assigned to placebo, patients assigned to the experimental drug with BRCA germline or somatic mutation (n = 196) had a median PFS of 16.6 months versus 5.4 months (HR, 0.23; P<.0001). Median PFS in the homologous recombination deficient (HRD) subgroup (n = 354) also favored rucaparib, 13.6 months versus 5.4 months (HR, 0.32; P<.0001).
The PFS advantage associated with rucaparib was more pronounced by independent review. Median PFS in the BRCA mutant cohort (secondary endpoint) was 26.8 months versus 5.4 months (HR, 0.20; P<.0001), 22.9 months versus 5.5 months (HR, 0.34; P<.0001) in the HRD cohort, and 13.7 months versus 5.5 months (HR, 35; P<.0001) in the ITT population.
Jonathan Ledermann MD, FRCP, professor of medical oncology at UCL Cancer Institute and UCL Hospitals, London, UK presented results from the double-blind, multinational phase III ARIEL3 trial. The study evaluated rucaparib as a maintenance therapy compared with placebo in women with high-grade recurrent ovarian cancer, including fallopian tube, or primary peritoneal carcinomas.
“Rucaparib maintenance treatment significantly improved PFS over placebo in the nested BRCA-mutant and HRD cohorts and in the overall ITT population,” he said. “In addition, PFS was improved with rucaparib maintenance in patients with BRCA wild-type LOH-high and LOH-low.
“Rucaparib maintenance therapy could be considered a new standard of care for women with in platinum sensitive ovarian cancer following a complete or partial response to second-line or later platinum-based chemotherapy,” Ledermann said.
Eligible patients had CA-125 less than the upper limit of normal, and platinum-sensitive disease with a demonstrated complete (CR) or partial response (PR) to the most recent platinum therapy. Enrollment placed no restriction on the size of residual tumor.
Patients were stratified according to homologous recombination DNA repair (HRR) status by next generation sequencing (NGS) mutation analysis, CR or PR, and by 6 to 12 months or >12 months progression-free duration after penultimate platinum. The cohort was then randomly assigned to 600 mg twice-daily rucaparib (n = 372) or placebo (n = 189).
The primary endpoint was investigator-assessed PFS in 3 prospectively defined nested subgroups: BRCA mutant with either a deleterious germline or somatic BRCA mutation, HRD comprising either BRCA mutant or BRCA wild-type/LOH high, and the ITT population of all-comers.
PFS as assessed by blinded independent central review (BICR), and according to LOH status in patients with BRCA wild-type ovarian cancer were key secondary endpoints.
Further analysis of efficacy in patients by LOH status showed that those with BRCA wild-type/LOH-high tumours had a median PFS of 9.7 months versus 5.4 months (HR, 0.44; (P<.0001) by investigator assessment and 11.1 versus 5.6 months (HR, 0.55; P = .0135) by BICR median PFS was with rucaparib versus placebo, respectively.
Patients with BRCA wild-type/LOH-low showed the poorest median PFS by investigator review 6.7 vs 5.4 months; HR 0.58; P = .0049) and by BICR (8.2 vs 5.3 months; HR 0.47; P = .00002), though outcomes were still superior in patients assigned to rucaparib.
“Improvement in PFS, albeit less, was observed in subgroups of patients with BRCA wild-type ovarian cancer with both LOH-high and LOH-low tumors,” Ledermann said. “LOH is not able to separate unresponsive patients.”
The objective response rate (ORR) by RECIST in the ITT population was 18.4% with rucaparib versus 7.6% with placebo. Ten patients (7.1%) assigned to rucaparib had CR, 16 had PR (11.3%), 71 (50.4%) had stable disease (SD), and 38 (27.0%) had progressive disease (PD).
RECIST ORR in the HRD cohort was 27.1% with rucaparib versus 7.3% with placebo. With rucaparib, 10 (11.8%) patients had CR, 13 (15.3%) patients had PR, 43 (50.6%) patients achieved SD, and 18 (21.2%) experienced PD.
In the BRCA mutant cohort, the ORR was 37.5% with rucaparib versus 8.7% with placebo. In the rucaparib arm, 7 (17.5%) patients had CR, 8 (20.0%) patients had PR, 19 (47.5%) patients showed SD, and 5 (12.5%) experienced PD.
“The most common side effects were gastrointestinal and consistent with prior studies of rucaparib,” Ledermann pointed out.
All patients on rucaparib and 96.3% of placebo patients had at least one adverse event (AE), and 56.2% versus 14.8% of patients experienced at least 1 grade ≥3 AE, respectively. The most common grade ≥3 treatment-emergent AEs associated with rucaparib were alanine/aspartate aminotransferase increase (10.5%), asthenia (6.7%), vomiting (4%), and nausea (3.8%).
“Over time both alanine and aspartate aminotransferase concentration increases resolved and were not associated with abnormal increases in bilirubin or other criteria for drug-induced hepatotoxicity,” Ledermann said. “Furthermore, no case met Hy’s law for drug-induced liver injury.”
Treatment interruption and/or dose reduction due to an AE occurred in 70.7% of patients assigned to rucaparib and 10.6% of those assigned to placebo. Patients in the rucaparib were signficiantly more likely to discontinue treatment due to AEs (13.4% vs 1.6%). Two patients in the rucaparib arm died and 1 in the placebo arm died due to disease progression.
Ledermann J, Oza AM, Lorusso D, et al. ARIEL3: Phase 3, randomised, double-blind study of rucaparib vs placebo following response to platinum-based chemotherapy for recurrent ovarian carcinoma (OC). Abstract presented at: 2017 ESGO Congress; November 4-7, 2017; Vienna, Austria.