PARP inhibitors represent an important class of emerging therapies for the treatment of patients with ovarian cancer and possibly other malignancies, but many scientific questions about the underlying molecular mechanisms that these agents target must be answered before they can be fully employed in clinical practice.
Those observations were among the insights that Tamar Safra, MD, offered during her presentation Thursday. Safra, of the Oncology Gynecology Service at the Tel-Aviv Sourasky Medical Center Sackler School of Medicine in Israel, has investigated a range of therapeutic strategies in ovarian cancer, including PARP inhibitors.
At least six PARP inhibitors are under development in phase I-III clinical trials in ovarian cancer, including as monotherapy and in combination with chemotherapy or with other targeted agents, said Safra. These include olaparib, veliparib, rucaparib, niraparib, BMN-673, and CEP-9722.
Olaparib is the most advanced of these agents. AstraZeneca Pharmaceuticals, which is developing the drug, is seeking FDA approval for olaparib as a maintenance therapy for women with platinum-sensitive relapsed ovarian cancer with germline BRCA
In June, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted against accelerated approval for olaparib based on phase II study results indicating that olaparib reduced the risk of progression by 83% compared with placebo but did not improve overall survival. Instead, the panel said the agency should wait for results from the phase III SOLO-2 trial.
Safra was among the investigators who reported findings from the phase II olaparib trial in The Lancet
in July (2014;15:852-861). Median progression-free survival (PFS) for patients with BRCA mutations was significantly longer in the olaparib group than in the placebo group (11.2 months vs 4.3 months; P
<.0001), and the research team concluded that patients with BRCA
-mutant platinum-sensitive recurrent serous ovarian cancer would most likely benefit from the targeted agent.
During her presentation, Safra also noted that combination strategies with chemotherapy and other targeted agents also should be investigated. Patients treated with a combination of olaparib and the angiogenesis inhibitor cediranib resulted in median PFS of 17.7 months compared with 9 months for olaparib alone, according to research presented at the 2014 American Society of Clinical Oncology Annual Meeting (Liu J et al; abstract LBA5500).Mechanisms Explored
PARP inhibitors target the poly (ADP-ribose) polymerase (PARP) family of enzymes, whose key functions include the repair of damaged DNA. These agents specifically target the base excision repair pathway, “thereby allowing greater selectivity than traditional cytotoxic drugs,” said Safra. This mechanism, known as synthetic lethality
, is the best-known mechanism for PARP inhibitors, but there are other possibilities, said Safra.
Thus far, significant responses with PARP inhibitors have been reported among patients with germline mutations in the BRCA
DNA repair gene, resulting in extensive research into these agents in breast and ovarian cancers, noted Safra. She said from 15% to 18% of ovarian cancer is related to BRCA1/2
However, Safra said research findings increasingly suggest that PARP inhibitors may also be employed against sporadic high-grade serous ovarian cancer (HGS-OC) and other cancers with DNA repair deficiencies such as prostate, endometrial, and pancreatic malignancies.
Significantly, about 50% of HGS-OC tumors show disruption of homologous repair pathways, with germline or somatic mutations in at least eight genes as well as epigenetic silencing of pathway members, Safra said.
Identifying additional subgroups of patients who might benefit from the agents is among the many challenges and unanswered questions facing the development of PARP inhibitors in ovarian cancer, Safra said.
She also said no prospectively validated biomarkers for defective repair pathways and responsiveness to the novel agents have been identified; the mechanisms of resistance to PARP inhibitors must be further studied; and researchers must find out whether there are significant differences in safety and efficacy among the agents now under study.
In addition, she said other challenges include incorporating PARP inhibitors into the treatment paradigm for ovarian cancer and “the rational development of treatment regimens of combinations of chemotherapy” and PARP inhibitors.
In terms of toxicities, Safra said the main adverse events from the PARP inhibitor class are anemia, thrombocytopenia, and neutropenia. She said all of the agents cause nausea and, at times, vomiting. “This has been a dose-limiting factor for some patients and a limiting factor for treatment with combinations of cytotoxic agents and PARP inhibitors,” Safra said in her symposium abstract.