Clinical Practice Guidelines
This update refers to Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up. Ledermann JA, Raja FA, Fotopoulou C et al. Ann Oncol 2013; 24 (Suppl 6): vi24–vi32.
Chemotherapy in recurrent ovarian cancer, Targeted therapy
Following the results of the first randomised maintenance trial with olaparib demonstrating a significant improvement in progression-free survival (PFS), particularly in patients with a BRCA mutation , further data has emerged and three other phase III trials with other poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have been conducted [2-4]. Maintenance therapy after platinum-based chemotherapy (ChT) for recurrent ovarian cancer with niraparib, rucaparib or olaparib (tablet formulation) has a wider clinical benefit. A PFS benefit is seen with all three drugs, not only in tumours with a BRCA mutation [germline (gBRCA)] or somatic (sBRCA)] but also in BRCA wild-type tumours. The greatest improvement in PFS is seen in BRCA-mutated tumours; with PFS hazard ratios (HR) of 0.27 [95% confidence interval (CI) 0.17–0.41] median PFS 21.0 versus 5.5 months for niraparib in gBRCA patients ; HR 0.23 (95% CI 0.16–0.34) with a median PFS of 16.0 versus 5.4 months for rucaparib in tumour BRCA-positive (tBRCA) patients ; and HR 0.30 (95% CI 0.22–0.41) median PFS 19.1 versus 5.5 months for olaparib in tBRCA (combined gBRCA and sBRCA) patients . A significant but lesser benefit is seen in tumours testing positive by commercial HRD (homologous recombination deficient repair of DNA) assays but the significant PFS in HRD-negative patients, and ‘all comer’ analyses has led to European Medicines Agency (EMA) approval of all three PARP inhibitors as maintenance therapy in high-grade ovarian cancers irrespective of their BRCA status. For niraparib, in the non-g BRCA group that includes sBRCA patients, the HR is 0.45 (95% CI 0.34–0.61) with a median PFS of 9.3 versus 3.9 months . For rucaparib, in the intention to treat population, the HR is 0.36 (95% CI 0.30–0.45) with a median PFS of 10.8 versus 5.4 months . The olaparib tablet approval for non BRCA-mutated tumours is based on the subgroup analysis of Study 19 with a HR 0.54 (95% CI 0.34-0.85) and a median PFS of 7.4 versus 5.5 months . Data are not yet mature for overall survival apart from the first study (Study 19) where a non-significant prolongation in survival, HR 0.73 (95% CI 0.55‒0.95) was
seen for patients on olaparib. In this study, 11% patients (in BRCA-mutated and BRCA wild type groups) remaining on treatment for >6 years without disease progression .
Overall, maintenance therapy with a PARP inhibitor following platinum-based ChT is a new standard of care option in patients who do not require ChT with bevacizumab . The EMA has also approved rucaparib monotherapy for patients with a germline or somatic BRCA mutation who have received at least two lines of therapy and are unable to receive platinum-based treatment. This was based on a combined analysis of two phase II trials, ARIEL2 and Study 10, demonstrating a response rate of 53.8% (95% CI 43.8–63.5) with 8.5% and 45.3% of patients achieving a complete and partial responses, respectively. The median duration of response was 9.2 months (95% CI 6.6–11.6) .
Maintenance therapy with a PARP inhibitor (olaparib, niraparib or rucaparib) following a response to platinum-based therapy in patients with recurrent platinum-sensitive high-grade ovarian cancer is a new standard of care option, irrespective of BRCA status [I, A].
For patients with recurrent platinum-sensitive ovarian cancer and a BRCA mutation unable to receive platinum-based therapy, rucaparib monotherapy is an option [III, A].
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sensitive, recurrent ovarian cancer. N Engl J Med 2016; 375: 2154–2164. 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. Lancet Oncol 2017; 18: 1274–1284. 5. Friedlander M, Matulonis U, Gourley C et al. Long-term efficacy, tolerability and overall survival in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer treated with maintenance olaparib capsules following response to chemotherapy. Br J Cancer 2018; 119: 1075–1085.
6. Colombo N, Sessa C, du Bois A et al. ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease. Ann Oncol 2019; 30: 672– 705. 7. Oza AM, Tinker AV, Oaknin A et al. Antitumor activity and safety of the PARP inhibitor rucaparib in patients with high-grade ovarian carcinoma and a germline or somatic BRCA1 or BRCA2 mutation: Integrated analysis of data from Study 10 and ARIEL2. Gynecol Oncol 2017; 147: 267–275.