- Design
- Updated systematic review and frequentist random-effects network meta-analysis with CINeMA certainty assessment (PROSPERO CRD420251161933)
- Population
- 23 randomised controlled trials, 18,689 patients with metastatic hormone-sensitive prostate cancer, all-comer populations
- Primary outcome
- Progression-free survival, overall survival and severe adverse events across first-line combination regimens
- Effect
- Docetaxel + ARPI + ADT progression-free survival HR 0.66 (95% CI 0.43-1.01, moderate certainty); no triplet significantly improved overall survival overall; docetaxel triplet overall survival HR 0.76 (0.61-0.95, high certainty) in high-volume disease
Intensification in metastatic hormone-sensitive prostate cancer has moved fast and the question of who needs a triplet rather than a doublet has not kept pace. This updated network meta-analysis searched to March 2026 and included 23 randomised trials with 18,689 patients, restricting the network to all-comer populations and using the CINeMA framework to grade certainty.
In the all-comer network, docetaxel plus an androgen receptor pathway inhibitor plus androgen deprivation showed a clinically relevant but not statistically significant progression-free survival improvement over the inhibitor with deprivation alone (HR 0.66, 95% CI 0.43-1.01, moderate certainty), as did a PARP inhibitor triplet (0.55, 0.23-1.34, low certainty). No triplet achieved a statistically significant overall survival benefit over the doublet.
One subgroup did. In high-volume disease, adding docetaxel improved overall survival (HR 0.76, 0.61-0.95) with high certainty - the single firmest result in the analysis, and the one that should drive practice. Severe adverse event comparisons did not reach significance but were imprecise enough that a clinically meaningful increase in toxicity cannot be excluded.
Certainty was downgraded throughout for open-label designs, inconsistent prior docetaxel exposure across comparator arms, and imprecision - the PARP inhibitor estimates especially, resting on small phase 2 samples.
So the practical position holds: offer an androgen receptor pathway inhibitor with androgen deprivation to everyone, and add docetaxel where the disease is high volume and the patient is fit for it. Do not extend triplet therapy to low-volume disease on the strength of a non-significant progression-free survival signal. Biomarker-driven strategies from AMPLITUDE, CAPItello-281 and PSMAddition support intensification in selected populations, which is a different argument from intensifying everyone.
- Define disease volume before choosing a doublet or a triplet - it is the variable with high-certainty evidence
- Add docetaxel for high-volume disease in a patient fit for chemotherapy
- Do not offer triplet therapy in low-volume disease on progression-free survival signals alone
- Discuss toxicity honestly: the safety comparison was too imprecise to reassure
- Biomarker-selected intensification is a separate question from all-comer intensification
The statistics, in plain English
A hazard ratio of 0.66 with an interval of 0.43 to 1.01 just includes 1.0 - the point estimate is impressive and the data cannot exclude no benefit, which is why certainty was rated moderate rather than high. The PARP inhibitor interval, 0.23 to 1.34, spans a huge range and reflects small phase 2 samples. The one result to rely on is the high-volume overall survival figure (0.76, 0.61-0.95, high certainty), because the interval excludes 1.0 and CINeMA did not downgrade it. Network meta-analysis compares regimens never tested head to head by linking through common comparators, so inconsistency in prior treatment between trials, which the authors flag, weakens every indirect comparison.
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