Triplet therapy versus androgen receptor pathway inhibitor-doublet therapy in metastatic castration-sensitive prostate cancer: a real-world multicenter retrospective comparison
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Updated: Jan 25, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Fumihiko Urabe1, Takafumi Yanagisawa1, Wataru Fukuokaya1
1Department of Urology, The Jikei University School of Medicine, 3-25-8, Nishishimbashi, Minato-ku, Tokyo 105-8461, Japan.
Background:
Although pivotal trials have demonstrated the superiority of triplet therapy over androgen deprivation therapy (ADT)-docetaxel doublet therapy, direct comparisons between triplet and androgen receptor pathway inhibitor (ARPI)-ADT doublet therapy remain lacking in real-world practice. This study evaluated the comparative efficacy and safety of triplet versus ARPI-doublet therapy in patients with metastatic castration-sensitive prostate cancer (mCSPC).
Methods:
A total of 837 patients with de novo mCSPC treated between February 2018 and April 2025 were included: 121 received triplet therapy (darolutamide plus docetaxel with ADT), and 716 received ARPI-doublet therapy (abiraterone acetate, enzalutamide, or apalutamide with ADT). The primary endpoint was castration-resistant prostate cancer-free survival (CRPC-FS), and the secondary endpoints were progression-free survival 2 (PFS2) and treatment-related adverse events (TRAEs). Propensity score-based inverse probability of treatment weighting (IPTW) and multiple sensitivity analyses adjusted for baseline imbalances.
Results:
The median follow-up was 24 months. In the IPTW-adjusted analysis, triplet therapy significantly improved CRPC-FS compared with ARPI-doublet therapy (hazard ratio 0.52, 95% confidence interval 0.39-0.68; P < .001). Subgroup analysis demonstrated consistent benefits in patients with high-volume disease, while no CRPC events occurred in the low-volume subgroup. Sensitivity analyses using propensity score matching and truncated IPTW confirmed the robustness of these findings. Cancer-specific and overall survival were not assessable because of limited follow-up and few events in the triplet cohort. Regarding safety, triplet therapy was associated with higher rates of grade ≥ 3 TRAEs (48.8% vs 8.7%), mainly hematologic toxicities.
Conclusion:
Triplet therapy significantly prolonged CRPC-FS compared with ARPI-doublet therapy in patients with de novo mCSPC, particularly among those with high-volume disease. However, this benefit was accompanied by higher toxicity, underscoring the need to balance efficacy with safety. Longer follow-up is required to determine impacts on PFS2, cancer-specific survival, and overall survival.
Insights
Triplet therapy significantly improves castration-resistant prostate cancer-free survival in metastatic castration-sensitive prostate cancer patients compared to androgen receptor pathway inhibitor-doublet therapy, but with increased toxicity.
Area of Science:
- Oncology
- Urology
- Clinical Trials
Background:
- Pivotal trials show triplet therapy superiority over ADT-docetaxel, but real-world data comparing triplet vs. ARPI-ADT doublet therapy in mCSPC is limited.
- This study addresses the gap by evaluating comparative efficacy and safety in a real-world mCSPC population.
Purpose of the Study:
- To compare the efficacy and safety of triplet therapy versus ARPI-doublet therapy in patients with de novo metastatic castration-sensitive prostate cancer (mCSPC).
- To assess castration-resistant prostate cancer-free survival (CRPC-FS) as the primary endpoint.
Main Methods:
- Retrospective analysis of 837 de novo mCSPC patients (121 triplet, 716 ARPI-doublet).
- Propensity score-based inverse probability of treatment weighting (IPTW) and sensitivity analyses adjusted for baseline imbalances.
- Primary endpoint: CRPC-FS. Secondary endpoints: PFS2, treatment-related adverse events (TRAEs).
Main Results:
- Triplet therapy significantly improved CRPC-FS compared to ARPI-doublet therapy (HR 0.52, P < .001) in IPTW-adjusted analysis.
- Benefits were consistent in high-volume disease subgroups; no CRPC events occurred in the low-volume subgroup.
- Triplet therapy showed higher rates of grade ≥3 TRAEs (48.8% vs 8.7%), primarily hematologic toxicities.
Conclusions:
- Triplet therapy significantly prolongs CRPC-FS in de novo mCSPC, especially in high-volume disease.
- The efficacy benefit of triplet therapy is associated with increased toxicity, necessitating a balance between efficacy and safety.
- Longer follow-up is needed to evaluate impacts on PFS2, cancer-specific survival, and overall survival.
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