Improved Survival Outcomes with Androgen-Receptor-Axis-Targeted Therapies in Metastatic Castration-Sensitive Prostate Cancer

Introduction

Androgen-receptor-axis-targeted (ARAT) therapies and docetaxel are proven efficacious and safe adjuvants to ADT (Androgen Deprivation Therapy) in metastatic castration-sensitive prostate cancer (mCSPC) patients. However, data on the patients’ baseline clinical characteristics that could predict efficacy with ARATs, principally identified through subgroup analyses are lacking. These data could help in devising or refining of treatment algorithms or protocols to treat such patients on the basis of their presenting disease state and features in order to yield best patient outcomes in terms of overall survival (OS) and progression-free survival (PFS).

Aim

This meta-analysis aimed to identify the baseline clinical characteristics associated with differential benefit from ARATs, determine the pooled estimates of efficacy outcomes and analyze differences in pooled estimates of efficacy outcomes between subgroups.

Method

Study Design

• Systematic review and meta-analysis of randomized-controlled clinical trials (RCTs) searching PubMed, Cochrane library and EMBASE was carried out in accordance with the PRISMA guidelines
• RCTs comparing the efficacy of ARAT agent plus androgen deprivation therapy (ADT) and ADT alone
• Dichotomous baseline variables that were analyzed as predictors of either PFS or OS-HR included age, Gleason score, LDH levels, prostate specific antigen (PSA) levels, ECOG performance status, tumor volume according to CHAARTED criteria, presence of visceral metastasis and use of docetaxel

Endpoints

Primary Endpoints

• Pooled estimates of hazard ratios HRs) for progression of death (PFS-HRs) and hazard ratios for death (OS-HRs)

Secondary Endpoints

• Differences in pooled HR-PFS and HR-OS between subgroups on the basis of pertinent predictors such as given below:
  • Age: ≥ 65 or < 65 years
  • Gleason score: ≥ 8 or < 8
  • LDH: ≥ Median or < Median
  • PSA: ≥ Median or < Median
  • ECOG score: 0 or > 0
  • Visceral metastases: Yes / No
  • High risk disease (as per CHAARTED definition): Yes / No
  • Prior docetaxel therapy: Yes / No

Results

• The cohort comprised 5427 mCSPC patients enrolled in 5 phase 3 RCTs – viz, LATITUDE, ARCHES, ENZAMET, STAMPEDE & TITAN trials, who were assessed for OS (Overall Survival) and PFS (Progression-free survival)
• Pooled OS-HR and pooled PFS-HR was 0.66 (95% confidence interval: 0.60 – 0.74) and 0.46 (95% confidence interval: 0.40 – 0.53) respectively
• Significant heterogeneity for OS-HR was observed in men who had been pretreated or concurrently treated with docetaxel as compared to men who were na?ve to docetaxel (interaction OS-HR 1.77, 95% confidence interval: 1.12 – 2.77; p=0.0134)
• The PFS outcomes with ARAT agents were worse in men with high disease burden (defined as per CHAARTED criteria) as compared to those with low disease burden (interaction PFS-HR 1.27, 95% confidence interval: 1.01 – 1.59; p=0.0395)
• The PFS benefit was less in men with visceral metastasis as compared to those with visceral metastasis (interaction PFS-HR 1.35, 95% confidence interval: 1.02 – 1.79; p=0.0347)
• There was also a borderline association of prior treatment with docetaxel with decreased PFS (interaction PFS-HR 1.34, 95% confidence interval: 1.00 – 1.56; p=0.051)

Conclusion

• Androgen-receptor-axis-targeted (ARAT) agents improve the overall survival outcomes in patients with metastatic castration-sensitive prostate cancer.
• Concurrent or sequential use of both docetaxel and an ARAT agents, high volume disease (as defined by CHAARTED criteria) and visceral metastases predict greater risk of progression and death with ARATs and thus, patients with these features are better candidates for non-ARAT therapies.

Crit Rev Oncol Hematol. 2020 Jul;151:102992. Doi: 10.1016/j.critrevonc.2020.102992.