CHICAGO — Frontline maintenance therapy with a PARP inhibitor more than doubled progression-free survival (PFS) in patients with platinum-sensitive ovarian cancer, a randomized, placebo-controlled trial showed.
In the subgroup of patients with homologous repair-deficient (HRD) tumors, maintenance therapy with rucaparib (Rubraca) led to a median PFS of 28.7 months versus 11.3 months with placebo. In the intention-to-treat (ITT) population, median PFS was 20.2 months with rucaparib and 9.2 months with placebo.
Maintenance with the PARP inhibitor after initial platinum-containing chemotherapy slowed disease progression compared with placebo in patients with HRD-positive and HRD-negative subtypes, reported Bradley Monk, MD, of the University of Arizona College of Medicine and HonorHealth Research Institute in Scottsdale, during the American Society of Clinical Oncology (ASCO) annual meeting.
“Rucaparib maintenance treatment improves progression-free survival, regardless of the molecular signature, and even in the HR-proficient subgroup,” he said. “Those with persistent disease after six cycles of therapy continue to respond. We observed no new safety signals. Patient-reported outcomes were consistent with placebo because we can manage adverse reactions by interruptions, dose reductions, and discontinuations. Overall survival data are immature.”
The full results were published simultaneously in the Journal of Clinical Oncology.
Impressive, But With Caveats
ASCO invited discussant Ernst Lengyel, MD, PhD, of the University of Chicago, found the results impressive but offered words of caution about PARP inhibitor maintenance for all patients, particularly those with HRD-proficient disease.
GlaxoSmithKline recently distributed a “Dear Health Care Provider” letter informing clinicians about unfavorable survival data from a European trial evaluating niraparib (Zejula) maintenance in recurrent platinum-sensitive ovarian cancer. According to the letter, an analysis of overall survival (OS) of the phase III ENGOT-OV16/NOVA showed a “possible OS detriment” with niraparib maintenance for patients without germline BRCA mutations, including the non-BRCA mutant/HRD-positive subgroup.
More concerning, Lengyel continued, is a survival analysis from the ARIEL 4 trial of maintenance rucaparib in platinum-sensitive relapsed or progressive ovarian cancer. The results showed a median OS of 19.6 months with rucaparib compared with 27.1 months in the placebo arm.
Acknowledging the hazards of cross-trial comparisons and that the ATHENA trial reported by Monk involved newly diagnosed ovarian cancer, Lengyel said, “I think we have to be careful with patients that are HRD proficient to give them a PARP inhibitor in the maintenance situation. These patients, especially if they had a complete radiologic and CA-125 response, will have a good chance to do well. Adding a PARP for these patients that don’t have any residual disease after frontline treatment will [lead to] significant side effects that we see with PARP inhibitors.”
Lengyel also pointed out that the HRD-negative subgroup in the ATHENA trial had a more modest improvement in median PFS with rucaparib.
Background, Key Results
Several studies have shown improved PFS with PARP inhibitors as first-line maintenance treatment for platinum-sensitive ovarian cancer in both recurrent and newly diagnosed disease. However, the optimal first-line maintenance strategy remains unclear, said Monk.
The international ATHENA trial evaluated single-agent rucaparib and a rucaparib combination strategy as maintenance therapy after response to platinum-based chemotherapy for newly diagnosed stage III-IV high-grade epithelial ovarian cancer. Monk reported findings for the evaluation of single-agent rucaparib versus placebo (ATHENA-MONO).
Eligible patients had newly diagnosed stage III-IV high-grade epithelial ovarian cancer and had achieved complete or partial response with platinum-doublet chemotherapy and surgery. They were randomized 4:1 to twice-daily rucaparib or placebo, and treatment continued for a maximum of 24 months or until disease progression, unacceptable toxicity, or death.
The primary endpoint was investigator-assessed PFS, analyzed in a step-down manner: the HRD-positive subgroup (BRCA mutant [BRCAmut] or BRCA wild type/loss of heterozygosity-high [BRCAwt/LOHhigh]) and the intention-to-treat population (all comers). PFS by blinded independent central radiologic review (BICR) was a secondary endpoint separate from the step-down analysis.
The ITT population comprised 528 patients, including 234 in the HRD-positive group. Analysis of the HRD-positive group showed that rucaparib reduced the PFS hazard by 53% (95% CI 0.31-0.72, P=0.0004). The 12-month PFS was 73.8% with rucaparib and 47.7% with placebo, and 24-month PFS was 56.3% versus 35.0%.
The ITT analysis showed a 48% reduction in the PFS hazard in favor of rucaparib (95% CI 0.40-0.68, P<0.0001). BICR assessments yielded similar differences in favor of rucaparib (HR 0.44, 95% CI 0.28-0.70 for the HRD-positive group; HR 0.47, 95% CI 0.36-0.63 for the ITT population).
Exploratory analyses of investigator-assessed PFS showed a consistent advantage for rucaparib:
- BRCAmut — HR 0.40, 95% CI 0.21-0.75
- BRCAwt/LOHhigh — HR 0.58, 95% CI 0.33-1.01
- BRCAwt/LOHlow — HR 0.65, 95% CI 0.45-0.95
BICR assessments of the subgroups yielded similar results.
An extensive analysis of exploratory subgroups failed to identify a group that did not benefit from rucaparib maintenance.
Grade ≥3 treatment-emergent adverse events (TEAEs) occurred more often with rucaparib (60.5% vs 22.7%). Treatment interruption and dose reduction because of TEAEs were also more common with rucaparib (60.7% vs 20.0% and 49.4% vs 8.2%, respectively). Twice as many patients in the rucaparib arm discontinued therapy because of TEAEs (11.8% vs 5.5%).
The most common TEAEs associated with rucaparib were gastrointestinal, asthenia/fatigue, elevated liver enzymes, anemia/decreased hemoglobin, neutropenia/neutrophil count, and thrombocytopenia/platelet count. All occurred more often as compared with the placebo arm.
During a discussion that followed the presentation, an unidentified audience participant asked Monk whether the results mean that all patients should receive a PARP inhibitor as part of frontline therapy.
“I just follow the ASCO guidelines and you just told us what the ASCO guidelines are: that all eligible patients should be considered for PARP maintenance therapy,” Monk replied. “This is nothing new. This just adds confidence for those who maybe are not following the guidelines.”
The study was supported by Clovis Oncology and the NIHR Cambridge Biomedical Research Center.
Monk disclosed relationships with Agenus, Akeso Biopharma, Amgen, Aravive, AstraZeneca, Bayer, Clovis Oncology, Eisai, Elevar Therapeutics, EMD Serono/Merck, Genmab/Seattle Genetics, GOG Foundation, Gradalis, ImmunoGen, Iovance Biotherapeutics, Karyopharm Therapeutics, Macrogenics, Merck, Mersana, Myriad Pharmaceuticals, Novocure, Pfizer, Puma Biotechnology, Regeneron, Roche/Genentech, Sorrento Therapeutics, Tesaro/GlaxoSmithKline, US Oncology, Vascular Biogenics, Advaxis, Array BioPharma, Lilly, Janssen, Morphotek, Novartis, and NuCana.