Repair of DNA damage is essential for the maintenance of genomic integrity. The proteins encoded by the
BRCA1 and
BRCA2 genes are involved in the repair of double-strand DNA breaks. The loss of function of these genes, commonly associated with ovarian cancer, makes cancer cells more dependent on alternative DNA repair processes such as single-strand DNA repair. PARP is an essential component of single-strand DNA repair, and its inhibition prevents cancer cells with deficient
BRCA function from repairing chemotherapy-induced DNA damage, making them more vulnerable to cytotoxic agents, a concept known in oncology as synthetic lethality [
26,
27].
The efficacy of olaparib as maintenance therapy has been demonstrated in randomized, double-blind, placebo-controlled, phase II (Study 19) and phase III (SOLO 2/ENGOT-Ov21) trials [
28‐
30]. In Study 19, conducted in 265 patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer, monotherapy with olaparib 400 mg twice daily (oral capsule formulation) was associated with a significantly longer median PFS compared with placebo (8.4 months versus 4.8 months; HR for progression or death, 0.35; 95% CI, 0.25–0.49;
P < 0.001) [
28]. No significant difference between groups was seen in OS. Adverse events more frequently reported in the group treated with olaparib included nausea, fatigue, vomiting, and anemia, which were mostly of grade 1 or 2. A preplanned analysis of Study 19 data by
BRCA mutation status showed that patients with platinum-sensitive relapsed serous ovarian cancer with a
BRCA mutation were more likely to benefit from treatment with olaparib [
29]. In the
BRCA-mutated group, median PFS was 11.2 months in patients treated with olaparib and 4.3 months in those receiving placebo (HR: 0.18; 95% CI, 0.10–0.31;
P < 0.0001). Median time to first subsequent therapy or death (TFST) and median time to second subsequent therapy or death (TSST) were also analyzed and were, respectively, 15.6 months (olaparib) versus 6.2 months (placebo) (HR: 0.33; 95% CI, 0.22–0.50;
P < 0.0001), and 23.8 months versus 15.2 months (HR: 0.44; 95% CI, 0.29–0.67;
P = 0.00013) in patients with a
BRCA mutation. A final OS analysis following the death of 203 (77%) of the 265 patients in Study 19, after more than 5 years of follow-up, revealed a longer OS of
BRCA-mutated patients receiving olaparib maintenance therapy, but the differences between groups did not reach statistical significance [
30]. The long-term exposure to olaparib was not associated with unexpected safety reports. The efficacy of olaparib (300 mg, twice daily, tablet formulation) as maintenance therapy has been further confirmed in the SOLO 2/ENGOT-Ov21 trial including 295 patients with platinum-sensitive, relapsed
BRCA-mutated ovarian cancer, who had received at least two lines of previous chemotherapy [
31]. Based on the data from the Study 19 and SOLO 2/ENGOT-Ov21 trial, the 2017 AIOM Italian guidelines for the treatment of ovarian carcinoma state that olaparib can be considered following chemotherapy as maintenance therapy in women with
BRCA mutations [
8].
Two additional PARP inhibitors will be available soon: niraparib, approved by the European Medicines Agency (EMA) in November 2017, and rucaparib (EMA approval procedure is ongoing). Niraparib was evaluated in the phase III ENGOT-OV16/NOVA trial in 553 women with platinum-sensitive, recurrent ovarian cancer and was shown to improve PFS substantially and significantly versus placebo, regardless of the presence or absence of germline
BRCA mutations or homologous recombination deficiency (HRD)-status, extending the potential of PARP inhibition beyond
BRCA-mutated cancers [
32]. Rucaparib was also evaluated in trials in which patients were categorized according to the presence or absence of
BRCA mutations and to HRD-status [
33,
34]. In the phase III ARIEL 3 trial, rucaparib significantly improved PFS over placebo in ovarian cancer patients who had achieved a response to platinum-based chemotherapy, regardless of
BRCA mutational status or HRD status [
33]. Overall, these findings provide further support to the potential of PARP inhibition in the maintenance setting. With regard to the selection of the most appropriate therapy, diagnostic companion testing and resource availability will likely play a central role.