Most patients with ovarian cancer present with advanced disease at diagnosis. Combination of a platinum drug with a taxane is standard of care for the systemic first-line treatment after surgery; however, disease recurrence is common in this population and many patients with recurrent ovarian cancer eventually develop platinum-resistant disease (recurring within six months after the last receipt of platinum-based chemotherapy or progressing while on a platinum-based chemotherapy).
Two potential therapeutic targets are DNA damage repair and angiogenesis pathways. A national Phase 2/3 study, sponsored by the National Cancer Institute, is comparing the combination of a PARP (poly ADP ribose polymerase) inhibitor that targets DNA damage repair and a VEGF inhibitor that inhibits angiogenesis, to standard of care chemotherapy.
“Recurrent ovarian cancer is not currently curable, so there is a real need for effective medications to manage it,” said Alaina Brown, M.D., assistant professor of gynecologic oncology at Vanderbilt University Medical Center and the local principal investigator of the study at Vanderbilt. “Most of the time we’re able to get these women to no evidence of disease in the up-front setting, but sadly the cancer often comes back.”
PARP inhibitors are used to cause synthetic lethality in cells with homologous recombination deficiency (HRD). They work by inhibiting the PARP protein, resulting in single stranded DNA breaks. Persistent single strand DNA breaks eventually lead to double stranded DNA breaks. Patients that have germline BRCA mutations or have tumors with somatic BRCA mutations or other HRD cannot repair the double stranded DNA breaks, which leads to cell (tumor) death.
The randomized trial, NRG GY005, is looking at the combination of cediranib, a small-molecule kinase inhibitor of VEGFR-1, -2, -3, and olaparib, a FDA-approved oral PARP-inhibitor, compared to cediranib alone, or to standard of care chemotherapy for the treatment of recurrent platinum-resistant ovarian cancer. “What we’re evaluating is whether the combination of these two drugs or cediranib alone is better than our standard-line chemotherapy,” Brown said.
A recent Phase 2 study found the combination cediranib/olaparib improved progression-free survival (PFS) compared with olaparib alone in women with recurrent platinum-resistant or -refractory ovarian, fallopian tube, or primary peritoneal cancer.
Next Steps for PARP Inhibitors
PARP inhibitors are currently FDA-approved for several settings: 1) treatment of recurrent platinum-resistant ovarian/fallopian tube/primary peritoneal cancer among patients with germline or somatic BRCA mutations; 2) treatment of recurrent platinum sensitive ovarian/fallopian tube/primary peritoneal cancer who have had a complete or partial response to a platinum based therapy for their recurrence; and 3) upfront maintenance therapy for patients with a germline or somatic BRCA mutation who have completed primary treatment of ovarian/fallopian tube/primary peritoneal cancer.
“If our results are positive, we may have an alternative regimen with the potential for increased tolerability in women with recurrent platinum-resistant or -refractory disease.”
The results of this trial could potentially produce practice-changing results. “PARPs have great promise and there’s already a significant role for them in treating ovarian cancer. We are looking to see if that role can be expanded further,” Brown said. “If our results are positive, we may have an alternative regimen with the potential for increased tolerability in women with recurrent platinum-resistant or -refractory disease.”