Key Highlights:
- A Phase 2 trial (NCT01972217; Study 8) investigating the combination of olaparib plus abiraterone versus placebo plus abiraterone as treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) who had previously received docetaxel (but were not selected based on homologous recombination repair mutation [HRRm] status) showed a significant radiographic progression-free survival (rPFS) benefit with combination olaparib plus abiraterone treatment.
- Subsequent exploratory and post hoc analyses of the impact of these treatments on quality of life showed that patient-reported outcomes relating to pain and health-related quality of life (HRQoL) were not different between treatment arms; these findings suggest that full doses of olaparib plus abiraterone could be combined in the treatment of mCRPC without impacting patient HRQoL.
- The recent Phase 3 PROpel trial evaluating olaparib plus abiraterone versus placebo plus abiraterone in first-line mCRPC (where similarly, patients were not selected based on their HRRm status) showed consistent clinical improvement to that observed in the Phase 2 Study 8 trial; additional HRQoL analyses will provide further insight.
The primary results of the trial showed that there was a significant radiographic progression-free survival (rPFS) benefit with the combination versus placebo plus abiraterone (median rPFS 13.8 months [95% CI 10.8–20.4] with olaparib plus abiraterone and 8.2 months [5.5–9.7] with placebo plus abiraterone; hazard ratio [HR] 0.65, 95% CI 0.44–0.97; P=0.034).1
More recently, this observation has been validated by the results of the phase 3 PROpel trial of olaparib plus abiraterone versus placebo plus abiraterone in first-line mCRPC (where similarly, patients were not selected based on their HRRm status). Consistent with the clinical improvement seen in the Phase 2 Study 8 trial, results of the PROpel study showed that median rPFS was significantly longer with olaparib plus abiraterone versus placebo plus abiraterone in patients recruited irrespective of HRRm status (24.8 vs 16.6 months; HR, 0.66; 95% CI 0.54–0.81; P<0.001; Figure 1).3 It has now also been reported in The Lancet Oncology that overall survival was numerically improved with olaparib plus abiraterone vs placebo plus abiraterone with a median OS of 42.1 months, 7.4 months longer compared with life-prolonging standard-of-care, abiraterone (HR 0.81; CI 0.67–1.00; P=0.054).4
Figure 1. Primary Results of Phase 2 Study 8 Trial and Phase 3 PROpel Trial in Patients Who Were Not Selected Based on Their HRRm Status.1,3
Previously reported data in patients with mCRPC showed that abiraterone (plus prednisone per the abiraterone label) treatment led to improvements in patient-reported health-related quality of life (HRQoL) and a significant delay in HRQoL deterioration compared with prednisone alone for those who had previously received docetaxel treatment.5 Another study showed that first-line abiraterone (plus prednisone) treatment delayed patient-reported pain progression and HRQoL deterioration compared with prednisone alone.6
HRQoL data for new treatment options, particularly for combination treatments which may cause additional toxicity, are valuable for helping patients and physicians make treatment decisions. This is exemplified in a recent small survey of patients with mCRPC (n=25) that showed that patients considered HRQoL to be the most important treatment benefit.7
Therefore, as the results in both the Study 8 and PROpel trials showed an efficacy benefit when olaparib was added to abiraterone treatment, it is important to understand the potential impact on HRQoL of introducing an additional treatment, while recognizing that the opportunity to see further positive benefit in this population would be limited due the progressive nature of mCRPC.
Full details of this exploratory analysis of patient-reported outcomes relating to pain and quality of life from the Study 8 trial of olaparib plus abiraterone versus placebo plus abiraterone were reported in The Lancet Oncology.2 Pain was assessed using the Brief Pain Inventory-Short Form (BPI-SF) worst pain and a separate single-item question on worst bone pain, while HRQoL was assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. Results from the EuroQol-5 five-dimension five level (EQ-5D-5L) assessment of pain and discomfort were also reported. Patients were asked to complete these assessments at weeks 4, 8, and 12, and then every 12 weeks until treatment discontinuation. The pain and HRQoL analyses conducted are listed in Table 1.
Table 1. Pain and HRQoL Analyses
|
Outcomes reported |
|
Least squares mean changes from baseline in BPI-SF worst pain, single-item worst bone pain, FACT-P total score and TOI |
|
Time to deterioration in BPI-SF worst pain, worst bone pain, FACT-P total score and TOI |
|
Time to improvement in BPI-SF worst pain, single-item worst bone pain, FACT-P total score and TOI |
|
Best response (improved, no change, deterioration) for FACT-P total score |
|
Assessment of the EQ-5D-5L pain and discomfort domain |
Results showed that least squares mean changes from baseline for BPI-SF, single-item worst bone pain, and FACT-P trial outcome index (TOI) scores remained stable over time. The analyses also found that time to deterioration in pain, and improvement in the pain and discomfort domain of the EQ-5D-5L were similar for both treatment groups.
Overall, these analyses showed that there was no significant difference in pain or HRQoL between the treatment arms. These results are not unexpected given the HRQoL benefit that has been observed with standard of care abiraterone and encouragingly suggest that HRQoL is maintained with combination treatment.5,6
This Phase 2 study included only exploratory and post hoc analyses of quality of life, but they give important early insights to indicate that full doses of olaparib plus abiraterone could be combined in the treatment of mCRPC without impacting patient quality of life.
HRQoL results from the Phase III PROpel trial were presented at ASCO 2023 and similarly show no clinically meaningful impact on HRQoL with intensification of therapy by addition of olaparib to current standard of care, abiraterone. Importantly, there were clinically meaningful improvements in exploratory post hoc patient-centric endpoints that assess impact following study treatment, such as delayed time to cytotoxic chemotherapy in the ITT population.8
Olaparib is currently approved in Europe as monotherapy for the treatment of adult patients with mCRPC and BRCA1 or BRCA2 mutations who have progressed following prior therapy that included a new hormonal agent and in the USA for patients with mCRPC who have previously experienced disease progression following treatment with enzalutamide or abiraterone and have mutations in homologous recombination repair genes. Abiraterone is approved in combination with prednisone for the treatment of patients with mCRPC in Europe and the USA. The combination of olaparib plus abiraterone and prednisone or prednisolone has recently been approved in Europe for the treatment of adult patients with mCRPC in whom chemotherapy is not clinically indicated and in the USA for adult patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) mCRPC, as determined by an FDA-approved companion diagnostic test.
Therefore, as the combination of olaparib plus abiraterone with prednisone or prednisolone becomes available for clinical use, HRQoL analyses that assess this combination, such as those reported from the Phase 2 Study 8 trial2 and the Phase 3 PROpel trial, will become important evidence to support treatment decisions.8
Acknowledgements:
This study was funded by AstraZeneca and is part of an alliance between AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Medical writing assistance was provided by Laura Smart MChem for Mudskipper Business Ltd, funded by AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Written by:
- Fred Saad, MD FRCS, Centre Hospitalier de l’Université de Montréal, Montreal, QC, Canada
- Noel Clarke, MBBS, ChM, FRCS, The Christie and Salford Royal Hospitals, Manchester, UK
- Clarke N, Wiechno P, Alekseev B et al. Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 2018;19:975-86.
- Saad F, Thiery-Vuillemin A, Wiechno P et al. Patient-reported outcomes with olaparib plus abiraterone versus placebo plus abiraterone for metastatic castration-resistant prostate cancer: a randomised, double-blind, phase 2 trial. Lancet Oncol 2022;23:1297-307.
- Clarke NW, Armstrong AJ, Thiery-Vuillemin A et al. Abiraterone and Olaparib for Metastatic Castration-Resistant Prostate Cancer. NEJM Evidence 2022;1:EVIDoa2200043.
- Saad F, Clarke NW, Oya M et al. Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival results of a randomised, double-blind, phase 3 trial. Lancet Oncol 2023;24:1094-108.
- Harland S, Staffurth J, Molina A et al. Effect of abiraterone acetate treatment on the quality of life of patients with metastatic castration-resistant prostate cancer after failure of docetaxel chemotherapy. Eur J Cancer 2013;49:3648-57.
- Basch E, Autio K, Ryan CJ et al. Abiraterone acetate plus prednisone versus prednisone alone in chemotherapy-naive men with metastatic castration-resistant prostate cancer: patient-reported outcome results of a randomised phase 3 trial. Lancet Oncol 2013;14:1193-9.
- Jones RJ, Collacott H, Morgans AK et al. Preferences and perceptions of patients with metastatic castration-resistant prostate cancer for treatments and biomarker testing: An international qualitative study. Journal of Clinical Oncology 2022;40:63.
- Thiery-Vuillemin A, Saad F, Oya M et al. Health-related quality of life (HRQoL) and pain outcomes for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) who received abiraterone (abi) and olaparib (ola) versus (vs) abi and placebo (pbo) in the phase III PROpel trial. Journal of Clinical Oncology 2023;41:5012-.