The results of three eagerly anticipated trials on the use of PARP inhibitors in ovarian cancer signal a big step forward in the treatment of women with advanced ovarian cancer, regardless of their BRCA status.
Late-breaking results of the phase III PAOLA-1/ENGOT-ov25 trial revealed that treatment with the PARP inhibitor olaparib in combination with bevacizumab significantly extended progression-free survival in patients with advanced ovarian cancer with and without a BRCA mutation.
The international trial led by Professor Isabelle Ray-Coquard, Centre Leon Bérard, Université Claude Bernard, Lyon, France enrolled 806 patients with stage III/IV ovarian cancer and partial or complete response to standard platinum-based chemotherapy and bevacizumab.
After completing first-line chemotherapy, patients were randomly allocated 2:1 to olaparib or placebo, in addition to bevacizumab. They received olaparib for up to 24 months and bevacizumab for 15 months in and the primary outcome was investigator-assessed progression-free survival.
The median follow-up was 24 months in the olaparib arm and 22.7 months in the placebo arm. Median progression-free survival was 22.1 months in the olaparib group and 16.6 months in the placebo group (hazard ratio 0.59; 95% confidence interval 0.49–0.72; p<0.0001).
“This study reports the greatest hazard ratio (0.59) and the longest progression-free survival we have ever seen…Patient selection was not restricted by surgical outcome or BRCA mutation status, so participants represent the general population of women with advanced ovarian cancer,” said Prof. Ray-Coquard who is also president of the GINECO group.
“Previous studies of relapse have suggested benefits from combining anti-angiogenic agents and PARP inhibitors and today’s results appear to support this.”
In pre-specified subgroup analyses, the progression-free survival benefit of olaparib versus placebo was even more pronounced in patients with a BRCA mutation and in those with homologous recombination deficiency (HRD), with hazard ratios of 0.31 and 0.33, respectively.
Median progression-free survival with olaparib reached 37.2 months in patients with a BRCA mutation and in patients with HRD.
“The results in HRD patients without a BRCA mutation identify, for the first time, a patient population with greater clinical benefit from olaparib when added to bevacizumab,” said Prof. Ray Coquard.
The safety profile of olaparib in combination with bevacizumab was generally consistent with previous trials and the addition of olaparib did not impact on bevacizumab tolerability or quality of life.
Four trials represent a milestone for ovarian cancer patients
Presented at the same presidential symposia the PRIMA trial showed that the PARP inhibitor niraparib given after completion of first-line chemotherapy significantly improved progression-free survival.
And the VELIA/GOG-3005 trial, which integrated veliparib with first-line chemotherapy then continued as maintenance treatment, also significantly extended progression-free survival regardless of response to first-line treatment.
According to invited commentator Dr Ana Oaknin, from the Vall d´Hebron Institute of Oncology (VHIO), Barcelona, the trials, together with the SOLO-1 trial, which all integrated PARP inhibitors in first-line treatment, were a milestone for patients.
“After decades studying different chemotherapy approaches, it is the first time we have meaningfully prolonged progression-free survival and hopefully we will improve long-term outcome,” she said, adding that the trials should be compared with caution as there were important and intrinsic differences.
“The five-year overall survival for ovarian cancer is around 45% and we need strategies to improve that figure. I think the next approach is to incorporate immunotherapy as part of first-line therapy. Ongoing trials are expected to report in two to three years,” she concluded.