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First-line maintenance with olaparib monotherapy and in combination bevacizumab increases survival in advanced ovarian cancer

Over 75% of patients with ovarian cancer are diagnosed at an advanced stage, as early-stage disease is usually asymptomatic.1,2 The prognosis of patients with advanced ovarian cancer is very poor, and relapsed ovarian cancer is generally incurable, emphasizing the requirement for durable first-line therapies that delay response and improve survival.3, 4

Approximately 20% of ovarian cancer cases are characterized by a BRCA mutation, and half of tumors are homologous recombination deficiency (HRD)-positive.5,6 The poly (ADP-ribose) polymerase (PARP) inhibitor, olaparib, is approved as frontline maintenance therapy for advanced ovarian cancer. Initially, olaparib was approved for use as a single-agent for maintenance in patients with germline or somatic BRCA mutations, based on primary analysis results of the Phase III SOLO-1 (NCT01844986) trial.7 Following the primary results of the Phase III PAOLA-1 (NCT02477644) trial, olaparib was additionally approved in combination with bevacizumab for patients with HRD-positive tumors, including those without a BRCA mutation.8,9 7-year and 5-year follow-up results of the Phase III SOLO-1 and PAOLA-1 trials, respectively, were presented at the European Society for Medical Oncology (ESMO) 2022 Congress, demonstrating long-term remission with olaparib as first-line maintenance therapy for HRD-positive advanced ovarian cancer.10,11

The Phase III SOLO-1 trial included 391 patients with newly diagnosed stage III-IV, BRCA-mutated ovarian, primary peritoneal, or fallopian tube cancer who had responded to first-line platinum-based chemotherapy. Patients were randomized 2:1 to receive maintenance olaparib (n=260) or placebo (n=131) for up to 2 years. The median duration of maintenance was 24.6 months in the olaparib arm and 13.9 months in the placebo arm and median follow-up was 88.9 months and 87.4 months, respectively.10 The primary endpoint of SOLO1 was progression-free survival (PFS). At 5 years follow-up, median PFS was 56.0 months with olaparib versus 13.8 months with placebo. Given that the majority of deaths occur 5-10 years after diagnosis, a descriptive analysis of overall survival (OS) as a secondary endpoint was performed 7 years following randomization. A clinically meaningful improvement in OS was observed with olaparib versus placebo, reducing the risk of death by 45% (HR of 0.55; 95% CI 0.40-0.76; nominal p=0.0004). Median OS was not reached with olaparib versus 75.2 months with placebo.

Nicoletta Colombo, MD, PhD, of the Istituto Europeo di Oncologia, Milan, Italy, comments that:

“This is the first time, together with PAOLO-1, demonstrating impressive improvement in overall-survival with the use of olaparib in the maintenance treatment after front-line chemotherapy.”

The Phase III PAOLA-1 study included 535 patients with newly diagnosed ovarian cancer who had responded to platinum-based chemotherapy. Patients were randomized 2:1 to receive olaparib plus bevacizumab (n=537) or placebo plus bevacizumab (n=269). The primary outcome was efficacy by PFS, and a key secondary outcome was OS. The primary analysis revealed the addition of olaparib to maintenance bevacizumab significantly increased PFS (HR 0.59, 95% CI 0.49–0.72; P<0.001), particularly in patients with HRD-positive tumors. Updated 5-year follow-up results of the Phase III trial demonstrated a median OS with olaparib plus bevacizumab versus bevacizumab alone of 56.5 months versus 51.6 months, respectively, in the intent-to-treat population. This increase was not statistically significant. However, a pre-specified descriptive analysis revealed a statistically significant OS benefit with olaparib plus bevacizumab versus bevacizumab alone in patients with HRD-positive tumors. 65.5% of patients treated with olaparib plus bevacizumab were alive at 5 years versus 48.4% of those treated with bevacizumab plus placebo, reducing risk of death by 38% (HR 0.62, 95% CI 0.45–0.85; OS at 5 years, 65.5 vs 48.4%), whilst no benefit was seen in patients with HRD-negative tumors. Additionally, 46.1% of patients remain progression free with the treatment combination compared to 19.2% treated with bevacizumab alone.11

The long-term follow-up data from SOLO-1 and PAOLA-1 highlight the importance of precision medicine and biomarker testing for HRD status in patients with ovarian cancer, demonstrating long-term remission can be achieved with olarparib in patients with HRD-positive tumors, enhancing the potential for the cure in this patient population.

References:

  1. Torre LA, Trabert B, DeSantis CE, et al. Ovarian cancer statistics, 2018. CA: A Cancer Journal for Clinicians. 2018;68(4):284–96. 
  2. Cancer of the ovary – cancer stat facts. SEER. Available from: https://seer.cancer.gov/statfacts/html/ovary.html
  3. Kemp A. Lynparza in combination with bevacizumab, and as a monotherapy, demonstrates clinically meaningful survival benefit in 1st-line advanced ovarian cancer across two Phase III trials. Available from: https://www.astrazeneca.com/media-centre/press-releases/2022/lynparza-in-combination-with-bevacizumab-demonstrates-clinically-meaningful-survival-benefit-in-advanced-ovarian-cancer.html
  4. Kahl KL. Long-term follow-up supports Olaparib maintenance therapy use in newly diagnosed advanced, BRCA+ ovarian cancer. Cancer Network. Cancer Network; 2022. Available from: https://www.cancernetwork.com/view/long-term-follow-up-supports-olaparib-maintenance-therapy-use-in-newly-diagnosed-advanced-brca-ovarian-cancer
  5. Pothuri B. BRCA1- and BRCA2-related mutations: therapeutic implications in ovarian cancer. Ann of Oncol. 2013;24(8):822-827.
  6. Bonadio RR, Fogace RN, Miranda VC, et al. Homologous recombination deficiency in ovarian cancer: A review of its epidemiology and Management. Clinics. 2018;73. 
  7. Lynparza approved in the EU for 1st-line maintenance treatment of BRCA-mutated advanced ovarian cancer. Available from: https://www.astrazeneca.se/media/pressmeddelanden/svenska_pressmeddelanden/2019/lynparza-approved-in-the-eu-for-1st-line-maintenance-treatment-o.html
  8. Arora S, Balasubramaniam S, Zhang H, Berman T, et al. FDA approval summary: Olaparib monotherapy or in combination with bevacizumab for the maintenance treatment of patients with advanced ovarian cancer. The Oncologist. 2020;26(1). 
  9. Slater H. FDA approves expanded Olaparib indication to include combination with bevacizumab [Internet]. Cancer Network. Cancer Network; 2020. Available from: https://www.cancernetwork.com/view/fda-approves-expanded-olaparib-indication-include-combination-bevacizumab
  10. DiSilvestro P, Banerjee S, Colombo N, et al. 517o overall survival (OS) at 7-year (y) follow-up (F/U) in patients (PTS) with newly diagnosed advanced ovarian cancer (OC) and a BRCA mutation (brcam) who received maintenance Olaparib in the solo1/gog-3004 trial. Annals of Oncology. 2022;33. 
  11. Ray-Coquard IL, Leary A, Pignata S, et al. LBA29 final overall survival (OS) results from the phase III paola-1/ENGOT-OV25 trial evaluating Maintenance Olaparib (OLA) plus bevacizumab (BEV) in patients (PTS) with newly diagnosed Advanced ovarian cancer (AOC). Annals of Oncology. 2022;33. 

Written by Ellie Jackson