We’re excited to share results of three recent studies that provide hope for women with newly diagnosed ovarian cancer. The studies, reported at the annual meeting of the European Society of Medical Oncology and two of which were published in the New England Journal of Medicine recently, show that three different types of PARP inhibitors (niraparib, veliparib, and olaparib) are effective at delaying recurrence of disease for all women with ovarian cancer, regardless of BRCA1/2 mutation status. PARP inhibitors are a class of drugs that have been shown to be effective for treatment of cancers that have mutations in BRCA1, BRCA2, and other genes that are needed to repair damage to DNA through a cellular process called homologous recombination.
The new studies come at the heels of several FDA and European agency approvals over the past few years for the use of PARP inhibitors to treat women in the upfront and recurrent disease settings who have mutations in BRCA1, BRCA2, or other defects in homologous recombination. The studies show significant benefit of the PARP inhibitors for all women with ovarian cancer, not only for women with BRCA1/2 mutations and other homologous recombination defects.
These results are provocative and promising in that they demonstrate that there appears to be benefit using PARP inhibitors in women with newly diagnosed ovarian cancer either in combination with and following chemotherapy in the case of veliparib or following chemotherapy in the case of niraparib and olaparib. Importantly, these are the first studies that evaluate these drugs in women with and without BRCA mutations in the upfront setting and show improvement in progression free survival (PFS – the amount of time before disease comes back) in women who are homologous recombination deficient without BRCA mutations.
I would anticipate that based on these studies we will see an expansion in the use of PARP inhibitors for patients which will allow us to incorporate this promising class of drugs into more patients we see in the clinic facing their initial treatment for ovarian cancer. This is exciting news for ovarian cancer patients, where five year survival is about 45% and recurrence of disease remains alarmingly high.
PRIMA/GOG-3012 looked at PFS in women who were newly diagnosed with advanced ovarian cancer who responded to their initial treatment with platinum and received either PARP inhibitor (niraparib) or placebo as maintenance therapy. The study reported that women who had tumors with defects in homologous recombination (those with defects in BRCA1, BRCA2, and other genes) had much longer intervals before the cancer returned on niraparib maintenance therapy than on placebo (PFS of 21.9 months on niraparib maintenance and 10.4 months on placebo). Importantly, the study also showed that there was even benefit in women who were not homologous recombination deficient, with a PFS of 8.1 months in the niraparib group and 5.4 months in the placebo group, translating to a 32% reduction in the risk of progression. The study also analyzed overall survival at the 24 month interval and found that, while not statistically significant, there was a higher survival rate in the niraparib group (84%) as compared to the placebo group (77%).
VELIA/GOG-3005 evaluated newly diagnosed women with ovarian cancer for PFS after treatment (1) chemotherapy plus veliparib followed by veliparib maintenance (veliparib throughout), (2) chemotherapy plus veliparib followed by placebo maintenance, or (3) chemotherapy plus placebo followed by placebo maintenance. The study found that women who received veliparib with chemo, followed by veliparib maintenance had significantly longer PFS compared to women who received chemo plus placebo and placebo maintenance. As in other studies, women with BRCA1/2 mutations or other homologous recombination defects received more benefit and had longer PFS than women without. For example, women with BRCA1/2 mutations who had veliparib throughout had PFS of 34.7 months compared to 22 months for women with chemo alone. Interestingly, in the “intent to treat” population, which included 37% of women who were not BRCA mutation carriers or homologous recombination deficient, there was a PFS of 23.5 months with veliparib throughout compared to 17.3 months in the placebo group.
PAOLA (GINECO/EngOT-ov25) evaluated olaparib, a PARP inhibitor which was FDA approved to treat BRCA mutated patients with newly diagnosed ovarian cancer in December of 2018, in combination with an angiogenesis inhibitor (bevacizumab) in a broader group of patients which included patients who were not BRCA mutated and patients who were not homologous recombination deficient. As anticipated, the patients with tumors that had BRCA mutations had a significant improvement in PFS of 37.2 months compared to 21.7 months with placebo. Patients who had tumors with homologous recombination deficiency also derived benefit, with 28.1 month PFS in the treatment group compared to 16.6 months with placebo. However, olaparib had little effect in women who did not have BRCA-mutated tumor and were not HRD-positive. In this group, PFS was 16.9 months with olaparib and 16.0 months with placebo, suggesting that in women without these “biomarkers” there may not be a role for PARP inhibitors in the “upfront” setting.
European Society for Medical Oncology press releases on all three clinical trials:
Dan S. Veljovich, MD
Pacific Gynecology Specialists/Swedish Cancer Institute
Rivkin Center Board of Directors