Olaparib as maintenance treatment for patients with platinum-sensitive relapsed ovarian cancer

Abstract

Poly (ADP-ribose) polymerase (PARP) inhibitors were developed with the intention of treating patients with homologous recombination repair deficiency (HRD), specifically for patients with tumours that harbour a BRCA mutation (BRCAm). Evidence from clinical trials to date has demonstrated that patients with a BRCAm derive the greatest benefit from PARP inhibitors. However, clinical studies have also shown that PARP inhibitors provide benefit to women with ovarian cancer who do not have a BRCAm. The recent updated approvals of olaparib, niraparib and rucaparib by the US Food and Drug Administration and the European Medicines Agency for the treatment of all platinum-sensitive relapsed (PSR) ovarian-cancer populations, regardless of their BRCAm status, support this. Long-term tolerability and efficacy of olaparib have been demonstrated in patients both with and without a BRCAm, with 13% of patients receiving maintenance olaparib for at least 5 years in one study, which is unprecedented in the relapsed ovarian-cancer setting (versus 1% on placebo). Further studies should be performed to elucidate which non-BRCAm patients are deriving benefit and what molecular processes are enabling this, so that patients continue to receive optimal treatment for their disease. Here, we review clinical and molecular markers of HRD, the long-term clinical safety and efficacy of PARP inhibitors in ovarian cancer, with a focus on olaparib and the current approved indications for PARP inhibitors, as well as guidance on treatment decisions for patients with PSR ovarian cancer.

Keywords: PARP inhibitor; niraparib; olaparib; platinum-sensitive relapsed ovarian cancer; rucaparib; targeted therapy.

Figure 1.

Study 19: TFST and TSST in all patients and according to BRCAm status. (a) TFST in the overall study population; (b) TFST in the BRCAm subgroup; (c) TFST in the non-BRCAm subgroup; (d) TSST in the overall study population; (e) TSST in the BRCAm subgroup; and (f) TSST in the non-BRCAm subgroup. BRCAm, BRCA mutation; BRCAwt, BRCA wild type; CI, confidence interval; HR, hazard ratio; TFST, time to first subsequent therapy; TSST, time to second subsequent therapy. Figure reproduced from Friedlander et al. (https://creativecommons.org/licenses/by/4.0/).

Figure 2.

Study 19: final overall survival in all patients and according to BRCAm status. (a) OS in overall study population; (b) OS in BRCAm subgroup; (c) OS in non-BRCAm subgroup. BRCAm, BRCA mutation; CI, confidence interval; HR, hazard ratio; OS, overall survival. Figure reproduced from Friedlander et al. (https://creativecommons.org/licenses/by/4.0/).

Figure 3.

Biomarker characterization in patients receiving olaparib for ⩾6 years in Study 19. ^*This patient was found to have a RAD51B mutation. ^$Two of five BRCAwt patients had no available Myriad HRD score result. BRCAm, BRCA mutation; BRCAwt, BRCA wild type; gBRCAwt, germline BRCA wild type; HRD, homologous recombination repair deficiency; HRRm, homologous recombination repair mutation; HRRwt, HRR wild type; sBRCAm, somatic BRCA mutation; tBRCA, tumour BRCA.

Figure 4.

Treatment algorithm for patients with platinum-sensitive relapsed ovarian cancer. ^*There are limited data on the efficacy of bevacizumab in the recurrence therapy setting for patients with platinum-sensitive disease previously treated with bevacizumab. PARP, poly (ADP-ribose) polymerase inhibitor.