Addition of androgen receptor-targeted agents to androgen-deprivation therapy and docetaxel in metastatic hormone-sensitive prostate cancer: a systematic review and meta-analysis

Abstract

Background: Androgen-deprivation therapy (ADT) historically represented the milestone for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC). Recently, combining androgen receptor-targeted agents (ARTA) or docetaxel with ADT significantly improved clinical outcomes in this setting. The efficacy of the combined use of an ARTA with docetaxel and ADT (triplet), however, was unknown, and often conflicting data derived from subgroup analysis of randomized phase III trials. In order to better define the benefits and risks of the triplet in mHSPC, we carried out a systematic review and meta-analysis of available clinical trials.

Methods: A literature search with no data restriction using Medline/PubMed, the Cochrane Library, and American Society of Clinical Oncology/European Society for Medical Oncology (ASCO/ESMO) Meeting abstracts was carried out up to April 2022. The meta-analysis was conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statements. Overall survival (OS) was the primary endpoint; progression-free survival (PFS) and safety were secondary endpoints. For OS and PFS, summary hazard ratios (HRs) were calculated; for safety, risk ratio (RR) was assessed. Random- or fixed-effects models were used, depending on studies heterogeneity.

Results: Five randomized clinical trials fulfilled the prespecified inclusion criteria. The triplet significantly improved OS (fixed-effect, HR = 0.74; P < 0.00001) and PFS (fixed-effect; HR = 0.50 for clinical PFS, HR = 0.49 for radiological PFS; P < 0.0001) compared with docetaxel plus ADT. We did not show heterogeneity between treatment efficacy and the disease burden, metachronous versus synchronous presentation, concomitant versus sequential strategy. Compared with docetaxel + ADT, the triplet did not increase the risk of adverse events (AEs) (RR = 1.00, P = 0.27 for any-grade AEs; RR = 1.13, P = 0.14 for severe AEs), except for severe hypertension (RR = 1.73, P = 0.001).

Conclusions: Emerging evidence supports the combination of an ARTA plus docetaxel and ADT in mHSPC patients. Given the availability of several strategies in this setting, clinical characteristics and drug safety profile may help clinicians select the appropriate treatment for mHSPC patients who are more likely to benefit from treatment intensification.

Keywords: abiraterone; darolutamide; docetaxel; mHSPC; meta-analysis; prostate cancer.

Figure 1

Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) flow chart of the selection process.

Figure 2

ARTA plus docetaxel and ADT versus docetaxel plus ADT: OS (A); subgroup analysis for disease burden—high versus low volume (B); subgroup analysis for synchronous versus metachronous disease (C); subgroup analysis for concomitant versus sequential strategy (D). ADT, androgen deprivation therapy; ARTA, androgen receptor targeted agent; CI, confidence interval; df, degrees of freedom; OS, overall survival; SE, standard error; Txt, docetaxel.

Figure 3

Safety profile ARTA plus docetaxel and ADT versus docetaxel plus ADT for (A) all-grade adverse events (AEs) and (B) severe AEs. ADT, androgen deprivation therapy; ARTA, androgen receptor targeted agent; CI, confidence interval; df, degrees of freedom; M-H, Mantel-Haenszel; Txt, docetaxel.

Figure 4

First-line therapy options for metastatic hormone-sensitive prostate cancer (mHSPC) patients. Dotted lines indicate future treatments possibly available after studies of docetaxel plus ARTA plus ADT. ADT, androgen deprivation therapy; ARTA, androgen receptor targeted agent; RT, radiotherapy.