Poly(ADP-ribose) Polymerase Inhibitors
The poly (ADP-ribose) polymerase (PARP), a new target in cancer therapy, is essential to repair single-strand DNA breaks through the base excision pathway. Homologous DNA repair defects arise in BRCA1 and BRCA2 mutation carriers where PARP inhibitors have shown preclinical efficacy. Phase 2 studies in ovarian cancer on the PARP inhibitors olaparib and iniparib have recently been reported.
An open-label, non-randomized, Phase 2 study enrolled 91 women, including 65 with recurrent, advanced, high-grade ovarian cancer, and treated them with olaparib 400mg twice daily as a single-drug therapy until disease progression.9 Among the 63 evaluable ovarian cancer patients, 29% (18 of the 63 patients; CI, 19–41) had overall objective responses, including 41% (7 of 17; CI, 22-64) with BRCA1 or BRCA2 status, and 24% (11 of 46; CI, 14–38) with non-BRCA status. All of the treated patients had at least one AE, with the most common AEs being fatigue, nausea, vomiting, decreased appetite, and abdominal distension.
A second Phase 2 study of olaparib used a randomized, double-blind design to compare olaparib to placebo by enrolling 265 patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer who had received two or more platinum-based regimens and then had either a partial or a complete response to their most recent platinum-based regimen.10 The patients received therapy either with olaparib 400mg twice daily or with placebo. The median PFS of 8.4 months in the olaparib group was significantly longer (P<0.001) than the 4.8 months in the placebo group. The olaparib group had a higher incidence of nausea, fatigue, vomiting, and anemia than the placebo group. The olaparib group had seven grade 4 AEs (5.1% of patients), while the placebo group had two (1.6% of patients).
Two Phase 2 trials, one in platinum-sensitive and one in platinum-resistant recurrent ovarian cancer, were reported for the combination of the PARP inhibitor iniparib with gemcitabine and carboplatin.11,12 The platinum-sensitive patients had an ORR of 70.6%, with no relationship between ORR and BRCA status. The platinum-resistant patients had an ORR of 31.6% and a median PFS of 5.9 months.
Other Novel Agents in Ovarian Cancer
EC145 is a folic acid and desacetylvinblastine hydrazide conjugate that binds with high affinity to the folate receptor, which is expressed on most epithelial ovarian cancers.13 An international, randomized, open-label, Phase 2 study examined its use to treat women with platinum-resistant ovarian cancer. The patients received pegylated liposomal doxorubicin 50mg/m2 every 28 days with or without EC145 2.5mg three times a week on Weeks 1 and 3. Among the intent-to-treat population, the PFS was 21.7 weeks for the patients receiving EC145, and 11.7 weeks for those not receiving EC145 (P=0.031). Among the patients with tumors 100% positive for EC20, which is a folate-receptor-targeted imaging agent, the PFS was 24.0 weeks with EC145 treatment and 6.6 weeks without EC145 treatment (P=0.018).