Patient-reported outcomes with olaparib plus abiraterone versus placebo plus abiraterone for metastatic castration-resistant prostate cancer: a randomized, double-blind, phase 2 trial

Background

The results of this double-blind phase 2 trial showed that patients with metastatic castration-resistant prostate cancer receiving olaparib plus abiraterone versus placebo plus abiraterone had significantly improved progression-free survival. Here we present an exploratory analysis of pain and health-related quality of life (HRQOL).

Methods

This double-blind, randomized, placebo-controlled phase 2 trial was conducted at 41 urologic oncology sites in 11 countries in Europe and North America. Eligible patients were 18 years of age or older, had metastatic castration-resistant prostate cancer, and had previously received docetaxel and up to one additional line of prior chemotherapy. Metastatic castration-resistant prostate cancer was defined as an increase in prostate-specific antigen (PSA) concentration or other signs of disease progression despite anti-androgen therapy and serum concentrations of testosterone at castration levels (≤ 50 ng/dL), and with at least one metastatic cancer lesion on bone scan, CT scan, or MRI. Eligible patients were randomized (1:1) to receive oral olaparib (300 mg twice daily) plus oral abiraterone (1000 mg once daily) and prednisone or oral prednisolone ( 5 mg twice daily) or placebo plus abiraterone (1000 mg once daily) and prednisone or prednisolone (5 mg twice daily). Randomization was performed without stratification and using an interactive web or voice response system. A randomized treatment kit identification number was assigned sequentially to each patient as they became eligible. The primary endpoint (radiographic progression-free survival) has already been reported. HRQoL was a pre-specified exploratory patient-reported outcome. Patients were asked to complete the Brief Pain Inventory-Short Form (BPI-SF), worst single-item bone pain, Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire, and EuroQol-5 questionnaire five dimensions five levels (EQ -5D-5L) initial assessment, at weeks 4, 8 and 12, then every 12 weeks until discontinuation of treatment. Prespecified outcomes were change from baseline in BPI-SF worst pain, single-item worst bone pain, and FACT-P Total Outcome Index (TOI) scores, time to deterioration of BPI-SF worst pain and worst bone pain, and EQ-5D-5L pain and discomfort domain rating. All analyzes were exploratory and performed in the full analysis set (all randomly assigned patients, including patients who were randomly assigned but did not subsequently receive study treatment), at except for mean baseline and total change from baseline, for which we used the population that had a valid baseline and at least one post-baseline assessment. This trial is registered with Clinicaltrials.gov, NCT01972217, and is no longer recruiting patients.

Results

Between November 25, 2014 and July 14, 2015, 171 patients were assessed for eligibility. 29 patients were excluded and 142 were recruited and randomized to receive olaparib and abiraterone (n=71) or placebo and abiraterone (n=71). The data cut-off date was September 22, 2017. The median follow-up was 15 9 months (IQR 8 1–25 5) in the olaparib plus abiraterone group and 24 5 months (8 1–27 6 ) in the placebo plus abiraterone group. Compliance with the questionnaire was generally high (43-100%). The least-squares mean changes from baseline in worst BPI-SF pain, worst single-item bone pain, and TOI FACT-P remained stable across visits for patients in both treatment groups. treatment. The adjusted mean change in FACT-P TOI from baseline across all visits was −0 10 (95% CI −2 50 to 2 71) in the olaparib plus abiraterone group and −1 20 (−4 15 to 1 74) in the placebo plus abiraterone group (difference 1 30, 95% CI -2 70 to 5 30; p=0 52). Time to pain deterioration was similar in both groups (BPI-SF worst pain HR 0 90 [95% CI 0·62–1·32], p=0.30; worst bone pain HR 0 85 [0·59–1·22], p=0 18). Rates of improvement in the EQ-5D-5L pain and discomfort domain were similar in both groups from baseline to week 48, beyond which a higher proportion of patients in the olaparib plus abiraterone arm reported improvement compared to the placebo plus abiraterone group.

Interpretation

In these pre-specified exploratory analyses, there was no significant difference in pain or HRQoL when olaparib was added to abiraterone. In this phase 2 trial, a statistically significant radiographic progression-free survival benefit was observed with the combination of olaparib plus abiraterone. These results suggest that the improved survival benefits seen when olaparib is combined with abiraterone does not result in a different HRQOL compared to placebo plus abiraterone. Phase 3 studies are needed to validate these results.

Funding

AstraZeneca and Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

Comments are closed.