Highlights
- Triplet therapy with ARPI + Docetaxel + ADT significantly improves overall survival in synchronous high-volume mHSPC compared with doublets.
- ARPI + ADT doublet therapy offers the greatest benefit in low-volume and metachronous cases compared to ADT alone.
- Docetaxel doublet has no added benefit when ARPI is available and feasible.
- Evidence integrated from 11 high-quality phase 3 trials, evaluated with a living network meta-analysis framework.
Background
Metastatic hormone-sensitive prostate cancer (mHSPC) presents a heterogeneous prognosis, with disease burden quantified by metastatic volume and classified by timing of metastasis. Recent therapeutic advances include intensified systemic regimens such as androgen receptor pathway inhibitors (ARPIs) and docetaxel chemotherapy, either alone or in combination, alongside androgen deprivation therapy (ADT). However, optimal therapy selection requires careful stratification by disease characteristics. The living network meta-analysis by Riaz et al. addresses this gap, synthesizing evolving evidence to guide treatment decisions.
Study Design
This living systematic review and network meta-analysis employed the Living Interactive Evidence (LIvE) framework, incorporating 11 phase 3 randomized controlled trials (RCTs) involving 12,668 patients with mHSPC. Participants were categorized into four prognostic subgroups based on metastatic burden and metastasis timing: synchronous high-volume (SHV), synchronous low-volume (SLV), metachronous high-volume (MHV), and metachronous low-volume (MLV). Investigated interventions included ARPI-based regimens, docetaxel, and their combinations with ADT. The primary endpoint was overall survival (OS), with progression-free survival as a secondary measure. Bayesian and frequentist analytical methods enabled mixed treatment comparisons across subgroups.
Key Findings
Synchronous High-Volume (SHV)
In 5,171 patients (57% of analyzed cohort), triplet therapy (ARPI + Docetaxel + ADT) outperformed docetaxel doublet (HR 0.72; 95% CI 0.62–0.83) and ARPI doublet (HR 0.71; 95% CI 0.53–0.97), demonstrating robust OS advantage. This subgroup benefits most from aggressive upfront intensification, provided patients meet fitness criteria for docetaxel.
Synchronous Low-Volume (SLV)
Among 2,455 patients (27%), ARPI + ADT yielded significantly longer OS than ADT alone (HR 0.65; 95% CI 0.52–0.80). No statistical OS benefit was observed with triplet therapy versus ARPI doublet (HR 1.08; 95% CI 0.65–1.79), suggesting limited incremental value of adding docetaxel in low-volume synchronous disease.
Metachronous High-Volume (MHV)
In 589 patients (6.5%), neither triplet therapy nor ARPI doublet showed statistically significant OS improvement compared to other regimens. Hazard ratios versus ARPI doublet (HR 0.89; 95% CI 0.43–1.85) and docetaxel doublet (HR 0.90; 95% CI 0.60–1.36) reflect equivocal benefit. Therapy should be individualized, considering patient preferences and comorbidity.
Metachronous Low-Volume (MLV)
In 775 patients (8.5%), ARPI + ADT markedly improved survival compared to ADT alone (HR 0.43; 95% CI 0.29–0.64) and docetaxel doublet (HR 0.41; 95% CI 0.24–0.70). Triplet therapy offered no significant OS improvement over ARPI doublet (HR 1.56; 95% CI 0.40–6.25), reinforcing ARPI doublet as standard in this setting.
Safety and Limitations
The analysis did not uniformly account for patient-level factors influencing prescriber choice of docetaxel, such as performance status and comorbidity burden. Additionally, cross-trial differences in endpoint definitions and follow-up duration may impact comparisons. However, the LIvE methodology enables timely updates as new RCTs emerge.
Expert Commentary
These findings consolidate current clinical practice trends and align with evolving guidelines biasing toward ARPI doublet therapy as the preferred choice for most mHSPC patients. Triplet therapy’s superiority in SHV patients likely reflects greater synergy between agents in aggressive tumor phenotypes, whereas low-volume and metachronous cases gain minimal incremental value from chemotherapy. Importantly, avoiding docetaxel when ARPI is available reduces toxicity burden without compromising survival outcomes in these cohorts.
Conclusion
For mHSPC, treatment should be stratified by disease volume and timing of metastasis. Triplet therapy is recommended for fit SHV patients, while ARPI + ADT doublet should be the default for SLV, MHV, and MLV populations. This living meta-analysis framework ensures adaptability as evidence evolves, guiding precision oncology approaches in prostate cancer.
Funding and ClinicalTrials.gov
Study synthesized data from multiple phase 3 RCTs registered on ClinicalTrials.gov; primary citation: Riaz IB et al., Eur Urol. 2026 Jan;89(1):31–44. DOI: 10.1016/j.eururo.2025.09.007.
References
Riaz IB, Ahmed Naqvi SA, Faisal KS, He H, Rubab Khakwani KZ, Childs DS, Orme JJ, Ravi P, Singh P, Hussain SA, Chi K, Agarwal N, Merseburger AS, Davis ID, Armstrong A, Hussain MH, Smith M, Attard G, Tombal B, Fizazi K, James N, Omlin A, Gillessen S, Murad MH, Van Allen EM, Sweeney CJ, Bryce AH. Comparative Survival in Metastatic Hormone-sensitive Prostate Cancer by Volume of Disease and Timing of Metastasis: A Living Network Meta-analysis. Eur Urol. 2026 Jan;89(1):31-44.
