PARP Inhibitors Have Acceptable Toxicity Profiles and Have Shown Efficacy in Treatment of Ovarian Cancer

Ovarian cancer is the leading cause of death from gynecologic cancer. Surgical cytoreduction followed by platinum chemotherapy has been the established primary treatment for ovarian cancer historically but has been associated with a high frequency of early relapse. Recurrent disease is often treated with additional chemotherapy, which is rarely curative.

The management of ovarian cancer has shifted radically since poly (ADP-ribose) polymerase (PARP) inhibitors were added to the treatment armamentarium following the US Food and Drug Administration (FDA) approval of olaparib, niraparib, and rucaparib. Based on improved genetic testing for BRCA and homologous recombination deficiency alterations, this class of medications has rapidly moved into the first-line setting, enabling a personalized medicine approach. This is particularly important as patient selection can be precisely matched, based on the more than 15% of patients with high-grade serous ovarian cancer who are carriers of BRCA1 or BRCA2 germline mutations. The trials summarized in this article demonstrate that olaparib, niraparib, and rucaparib have acceptable toxicity profiles, have shown efficacy in treatment and maintenance settings, and have received FDA approval for specific indications within the ovarian cancer treatment setting.

In 2014, the FDA granted accelerated approval to olaparib for the treatment of ovarian cancer associated with specific BRCA genes. The approval was based on a phase 2 multicenter efficacy and safety trial of olaparib used to treat a wide range of BRCA mutation–associated tumors. The trial included heavily pretreated patients (N = 193) with ovarian cancer, 77% of whom possessed a BRCA gene germline mutation. The tumor response rate was 31.1%, median progression-free survival (PFS) was 7 months, and median overall survival was 16.6 months in the ovarian cancer cohort. In this study, regardless of anatomic organ of origin, the response to olaparib was observed across a range of cancer types, suggesting that PARP inhibitor therapy may be directed against BRCA-deficient cells.¹ Based on further studies that analyzed the safety and efficacy in a subgroup of patients with germline BRCA-mutated ovarian cancer who had received ≥3 prior lines of chemotherapy, the FDA approved olaparib as monotherapy.²

In 2017, the FDA approved olaparib as a maintenance therapy for recurrent, platinum-sensitive disease based on 2 clinical trials. The first of these was a phase 2, randomized, double-blind, placebo-controlled study of patients (N = 265) who were clinically enriched for PARP inhibitor treatment response markers. These patients had relapsed, platinum-sensitive, high-grade, serous ovarian cancer, yet were responsive to most recent treatment with platinum chemotherapy. PFS was significantly improved in the 400-mg twice-daily olaparib cohort (median 8.4 months) compared with the placebo cohort (median 4.8 months).³

In the second study, called SOLO-2, patients (N = 295) were randomized (2:1) to receive either 300 mg olaparib or a placebo twice daily; a statistically significant improvement in investigator-assessed PFS in patients randomized to receive olaparib was shown.⁴

In 2017, the FDA approved niraparib for maintenance treatment of patients with recurrent ovarian cancer who showed a complete or partial response to platinum-based chemotherapy regardless of BRCA status. Niraparib was shown to be safe and effective in the phase 3 randomized, double-blind NOVA trial, in which niraparib 300 mg was administered daily as maintenance treatment for patients with platinum-sensitive, relapsed ovarian cancer.⁵ Patients were eligible to receive therapy, and were divided into germline-mutated (gBRCA) and non–germline-mutated (non-gBRCA) cohorts. Testing of tissue samples was also conducted for patients in the non-gBRCA cohort in whom tumors had homologous recombination deficiency (HRD-positive subgroup). Of the 553 patients included in the study, 345 were in the non-gBRCA cohort and 201 were in the gBRCA cohort. Median PFS was 21 months in the niraparib group compared with 5.5 months in the placebo arm (P <.001) in the gBRCA cohort. In the non-gBRCA cohort, median PFS improvement attributed to niraparib treatment was 9.3 months versus 3.9 months in the placebo group. In the HRD-positive subgroup, the benefit appeared to be more pronounced, with the median PFS measured at 12.9 months in the niraparib group, versus 3.8 months in the placebo group (P <.001). FDA approval of niraparib as monotherapy was based on these results, making niraparib the first PARP inhibitor to be approved that does not require BRCA mutation.

The ARIEL3 study was a phase 3, randomized, double-blind, placebo-controlled trial that investigated the effect of rucaparib in patients with ovarian cancer who had been treated with ≥2 previous platinum-based chemotherapy therapy regimens and achieved a response to their most recent platinum-based therapy. Rucaparib significantly improved PFS in patients with platinum-sensitive ovarian cancer who had achieved a response to platinum-based chemotherapy across all primary analysis groups.⁶

PARP inhibitors demonstrated toxicity profiles that are manageable with appropriate delays and dose modifications, and efficacy in various ovarian cancer populations. Taken together, these studies suggest that PARP inhibitor therapy may potentially set a new standard of care for platinum-sensitive ovarian cancer patients who have had a complete or partial response to second-line or later platinum-based chemotherapy.

Source

Bahena-González A, Toledo-Leyva A, Gallardo-Rincón D. PARP inhibitors in ovarian cancer: evidence for maintenance and treatment strategies. Chin Clin Oncol. 2020;9:51.

References

1. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33:244-250.
2. Domchek SM, Aghajanian C, Shapira-Frommer R, et al. Efficacy and safety of olaparib monotherapy in germline BRCA1/2 mutation carriers with advanced ovarian cancer and three or more lines of prior therapy. Gynecol Oncol. 2016;140:199-203.
3. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366:1382-1392.
4. Pujade-Lauraine E, Ledermann JA, Selle F, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial [published correction appears in Lancet Oncol. 2017;18:e510]. Lancet Oncol. 2017;18:1274-1284.
5. Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375:2154-2164.
6. Coleman RL, Oza AM, Lorusso D, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial [published correction appears in Lancet. 2017;390:1948]. Lancet. 2017;390:1949-1961.