Olaparib as a maintenance therapy for ovarian cancer and its use in BRCA-related metastatic breast cancer
Olaparib as a maintenance therapy for ovarian cancer and its use in BRCA-related metastatic breast cancer
Janet M Manson, Touch Medical Media, London, UK

Olaparib (AZD2281) is a potent oral poly(ADP-ribose) polymerase (PARP) inhibitor that blocks DNA repair by trapping PARP at sites of DNA damage.1 In tumour cells with deficiencies in homologous recombination repair, such as those with BRCA1 or BRCA2 mutations (BRCAm), PARP inhibition leads to the formation of double-stranded DNA breaks that cannot be accurately repaired, resulting in synthetic lethality.1 Olaparib was the first PARP inhibitor to receive regulatory approval. In 2014, olaparib was licensed as a monotherapy by the US Food and Drug Administration (FDA) for patients with germline BRCAm advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. In the same year, olaparib was licenced by the European Medicines Agency (EMA) as a monotherapy for the maintenance treatment of patients with platinum-sensitive relapsed BRCAm high grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy.

Ovarian cancer has the highest mortality rate of all the gynaecological cancers.2 The standard treatment is surgery followed by six courses of platinum-based chemotherapy.2 Unfortunately, following completion of treatment approximately 80% of women with advanced ovarian cancer will have tumour progression or recurrence,3 and the 5-year survival rate for all types of ovarian cancer is 45%.4 To prolong remission duration and improve overall survival, maintenance therapy can be given to women with ovarian cancer who have achieved remission following surgery and induction chemotherapy. Based on results from Study 19 (NCT00753545),5 and SOLO-2 (NCT01874353),6 in 2017 the FDA granted approval to olaparib tablets for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy, regardless of BRCA status. A decision by the EMA on the licensing of olaparib for maintenance treatment in patients, irrespective of BCRA status, is expected in 2018. Olaparib was approved in Japan in early 2018 as a maintenance therapy for patients with platinum-sensitive relapsed ovarian cancer, who responded to their last platinum-based chemotherapy, regardless of their BRCA mutation status.

Study 19 was a phase II clinical trial that enrolled 265 patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer, regardless of BRCA status.5 Patients were randomised (1:1) to receive eight 50 mg capsules of olaparib, twice daily (equivalent to a daily dose of 800 mg) or placebo. Progression-free survival (PFS) was significantly longer with olaparib than with placebo (median: 8.4 months versus 4.8 months; hazard ratio [HR] for progression or death: 0.35; 95% confidence interval [CI]: 0.25 to 0.49; p<0.001). Irrespective of BCRA status, for women with ovarian cancer the risk of progression or death was reduced by 65% with maintenance olaparib versus placebo. In patients with BRCAm ovarian cancer, median PFS was significantly longer in the olaparib group than in the placebo group (11.2 months versus 4.3 months; HR: 0·18; 95% CI: 0·10–0·31; p<0·0001).7

In the phase III SOLO-2 study, 295 patients with recurrent germline BRCAm ovarian, fallopian tube or primary peritoneal cancer were randomised (2:1) to receive two 150 mg olaparib tablets, twice daily (equivalent to a dose of 600 mg) or placebo.6 Investigator-assessed median PFS was significantly longer with olaparib than in the placebo group (19.1 months versus 5.5 months; HR: 0·30; 95% CI: 0·22–0·41; p<0·0001). In patients with platinum-sensitive, relapsed, BRCAm ovarian cancer, maintenance treatment with olaparib showed a 70% reduction in the risk of progression or death.

In addition to its approval for use as a maintenanace therapy in ovarian cancers, olaparib became the first PARP inhibitor to be approved by the FDA for germline BRCAm metastatic breast cancer (MBC) in January 2018. This approval was based on data from the randomised, open-label, phase III OlympiAD trial, which investigated olaparib versus standard therapy with the physician’s choice of chemotherapy (capecitabine, eribulin or vinorelbine).8

The OlympiAD study was a randomized, open-label, phase III trial in which olaparib was compared with standard therapy in patients with germline BRCAm and human epidermal growth factor receptor type 2 (HER2)-negative MBC who had received no more than two previous chemotherapy regimens for metastatic disease.8 Results from the study found that olaparib significantly prolonged PFS compared with chemotherapy (median 7.0 months versus 4.2 months) and reduced the risk of disease progression or death by 42% (HR: 0.58; 95% CI: 0.43–0.80; p<0.001). In the olaparib group, the response rate was 59.9% compared with 28.8% in the standard therapy group. The study concluded that in patients with germline BRCAm and HER2-negative MBC, olaparib monotherapy provided a significant benefit over standard therapy.

These recent regulatory approvals for the use of olaparib for maintenance therapy in advanced ovarian cancer and in treating BRCAm HER2-negative breast cancer demonstrate that targeting the underlying genetic causes of a cancer can be a powerful tool for the development of new treatments with efficacy across different cancer types.

Support: This Insight article was supported by AstraZeneca.
Acknowledgements: Medical writing assistance was provided by Janet M Manson at Touch Medical Media.

References

1. O'Connor MJ. Targeting the DNA damage response in cancer. Mol Cell. 2015;60:547–60.
2. Mei L, Chen H, Wei DM, et al. Maintenance chemotherapy for ovarian cancer. Cochrane Database Syst Rev. 2013:CD007414.
3. Luvero D, Milani A, Ledermann JA. Treatment options in recurrent ovarian cancer: latest evidence and clinical potential. Ther Adv Med Oncol. 2014;6:229–39.
4. American Cancer Society. Survival Rates for Ovarian Cancer, by Stage. Available at: www.cancer.org/cancer/ovarian-cancer/detection-diagnosis-staging/survival-rates.html (accessed 26 February 2018).
5. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366:1382–92.
6. 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. Lancet Oncol. 2017;18:1274–84.
7. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 2014;15:852–61.
8. Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377:523–33.