Highlight
– An individual-patient data meta-analysis of 13 randomized trials (10,266 men; median follow-up 11.3 years) shows increasing oncologic benefit with longer ADT but diminishing returns beyond 9–12 months for many endpoints.
– Long-term ADT is associated with increased other-cause mortality (HR 1.28 for 28 vs 0 months), underscoring the need to weigh competing risks when selecting ADT duration.
– Suggested optimal ADT durations based on 10-year distant metastasis were: 0 months for patients with 1 intermediate-risk factor, 6 months for those with ≥2 intermediate-risk factors, 12 months for high-risk, and undefined for very-high-risk (favoring longer durations but with no clear plateau).
Background: disease burden and clinical question
Definitive radiotherapy combined with androgen deprivation therapy (ADT) is a cornerstone for many men with localized prostate cancer, particularly those with intermediate- and high-risk disease. Randomized trials conducted over the past three decades established that adding ADT to radiotherapy improves biochemical control, reduces distant metastases, and can prolong overall survival. However, trials tested widely varying ADT durations (from none to several years), and modern radiotherapy techniques and competing comorbidity risks complicate the translation of historical trial durations to individual patients seen today.
ADT carries non-oncologic harms including metabolic effects, cardiovascular risks, bone loss and quality-of-life consequences. Clinicians therefore need robust, individualized estimates of absolute and relative benefit to choose ADT duration that maximizes cancer control while minimizing harm. The meta-analysis by Zaorsky et al. (JAMA Oncology, 2025) provides the most comprehensive individual-patient data assessment to date of how ADT duration modifies outcomes when combined with definitive radiotherapy.
Study design and methods
This meta-analysis pooled individual patient data from 13 randomized phase 3 trials of radiotherapy with or without ADT, identified through systematic searches of trial registries and bibliographic databases covering 1980–2020. The analysis included 10,266 men (median age 70 years) with median follow-up 11.3 years. Most participants (72%) had National Comprehensive Cancer Network (NCCN) high-risk or very-high-risk disease. ADT exposure ranged from 0 to 36 months across trials.
Primary endpoint: overall survival (time from randomization to death or last follow-up). Secondary endpoints included biochemical recurrence, distant metastasis (DM), prostate cancer–specific mortality, and other-cause mortality. Analyses included both intention-to-treat and as-treated approaches. The investigators modeled the relationship between ADT duration and outcomes allowing nonlinear effects, and estimated numbers needed to treat (NNT) to prevent one DM at 10 years by prognostic subgroup.
Key findings
Overall patterns
Longer ADT durations were associated with improved cancer-related outcomes (reduced biochemical recurrence, distant metastasis, and prostate cancer–specific mortality). However, the benefits increased nonlinearly: the greatest incremental improvements were seen within the first 9–12 months of ADT, with diminishing relative gains thereafter for many endpoints.
In contrast, other-cause mortality increased in a near-linear fashion with longer ADT exposure. For example, the hazard ratio for other-cause death was 1.28 (95% CI, 1.09–1.50; P = .002) when comparing 28 months of ADT versus none. This implies a competing-risk trade-off: while cancer deaths and metastases fall with extended ADT, deaths from other causes rise.
Endpoint-specific nuances
– Distant metastasis and prostate cancer–specific mortality showed clear benefit with ADT; improvements were greatest when moving from 0 to around 6–12 months of ADT, after which incremental benefit tapered.
– Overall survival mirrored this pattern but was more strongly influenced by the increase in non–prostate cancer death with prolonged ADT.
Risk-group stratified implications and estimated optimal durations
The meta-analysis estimated optimal ADT durations using 10-year distant metastasis as a practical outcome. The recommended durations (based on modeled absolute and relative benefit) were:
– Patients with a single intermediate-risk factor: 0 months of ADT (i.e., radiotherapy alone may be sufficient).
– Patients with two or more intermediate-risk factors: 6 months of ADT.
– Patients with high-risk disease: 12 months of ADT provided an optimal balance in many cases, though the benefit curve did not fully plateau for some outcomes.
– Patients with very-high-risk disease: an “undefined” optimal duration in the sense that benefit continued to accrue beyond the durations tested (up to 36 months), so longer ADT (often 18–36 months) remains rational but must be weighed against increased noncancer mortality.
Number needed to treat and absolute effect sizes
The investigators calculated NNT to prevent one distant metastasis at 10 years by prognostic group. NNTs were lowest (i.e., greatest absolute benefit) for higher-risk groups and higher for lower-risk patients, reflecting the greater baseline risk of metastasis in high-risk disease. Because absolute numbers depend on baseline risk and background radiotherapy quality (dose, technique), clinicians should interpret NNTs in the context of individual patient risk and modern radiotherapy practice.
Safety and non-oncologic harms
The clear signal of increased other-cause mortality with longer ADT—observed across pooled trials—highlights the clinical importance of cardiovascular, metabolic, and bone health monitoring and mitigation strategies when ADT is prescribed. Quality-of-life impacts (fatigue, sexual dysfunction, hot flashes, body composition changes) were not the primary focus of this meta-analysis but remain critical to shared decision-making.
Expert commentary and guideline alignment
The meta-analysis helps reconcile long-standing questions about optimal ADT duration by quantifying diminishing marginal returns and highlighting competing risks. Current guideline frameworks already emphasize risk-stratified ADT durations: for example, NCCN recommends 4–6 months for intermediate-risk disease (shorter if favorable features) and 18–36 months for high-risk disease, with flexibility based on patient factors. The meta-analysis supports a nuanced approach: shorter ADT (or none) for favorable intermediate-risk disease, modestly longer ADT (≈6 months) for unfavorable intermediate risk, and individualized decisions for high–very-high risk where prolonged ADT offers continued oncologic benefits but at the cost of increased other-cause mortality.
Clinicians should also consider contemporary radiotherapy advances (dose-escalation, image guidance, hypofractionation, brachytherapy boost) that may improve local control, potentially modifying the absolute benefit of ADT at specific durations. Trials combining ADT with intensified systemic therapy (e.g., abiraterone or novel androgen receptor inhibitors) in high-risk localized disease have reported additional benefits but add complexity to duration decisions and toxicity profiles.
Limitations and generalizability
There are several important caveats when applying these results to current practice:
- Heterogeneity of trials: included trials span four decades with variation in radiotherapy dose, technique, ADT agents, and adherence. Many used older external-beam techniques and lower radiation doses than contemporary standards.
- Population mix: 72% of patients had high- or very-high-risk disease—results are therefore heavily influenced by higher-risk cohorts and may be less precise for truly low-risk populations.
- Endpoints and competing risks: trial definitions and ascertainment of biochemical failure and cause of death varied; meta-analysis methods mitigated but cannot eliminate heterogeneity.
- Non-oncologic outcomes: the data on cardiovascular events, metabolic endpoints, quality of life, and testosterone recovery were limited in pooled datasets, constraining individualized harm estimation.
- Contemporary systemic agents and combinations: more recent trials adding novel agents to ADT were not included and may change the risk–benefit calculus.
Clinical implications and practical recommendations
Using the meta-analysis findings together with guidelines and patient preferences, clinicians can consider the following approach:
- Favorable intermediate-risk (single risk factor): Radiotherapy alone is often reasonable; avoid routine ADT unless patient-specific factors argue otherwise.
- Unfavorable intermediate-risk (≥2 risk factors): Short-course ADT (~6 months) offers clear oncologic benefit with a favorable balance of harms.
- High-risk disease: Consider 12 months as a reasonable minimum in many men, acknowledging that some patients may derive additional benefit from longer courses (18–36 months), particularly those with very-high-risk features and long life expectancy, but clinicians must weigh competing comorbidities and increased noncancer mortality risks.
- Very-high-risk disease: Strong consideration for longer ADT (18–36 months) given continued oncologic benefit, with aggressive cardiovascular risk mitigation and shared decision-making about trade-offs.
- Always individualize: incorporate age, life expectancy, cardiovascular and metabolic comorbidities, bone health, patient preferences, and the specifics of radiotherapy (dose, boost strategy).
- Mitigate harms: baseline cardiovascular assessment, bone density evaluation, smoking cessation, exercise and nutrition counseling, and when appropriate, referral to cardiology or endocrinology for risk reduction.
Research gaps and future directions
Key areas for further study include prospective trials that integrate modern radiotherapy, contemporary systemic agents, and explicit cardiovascular risk-reduction strategies; characterization of ADT-related non-oncologic mortality mechanisms; and research into biomarkers that predict ADT sensitivity to better personalize duration. Patient-centered outcomes (quality of life, sexual function, cognition) deserve parallel emphasis.
Conclusion
The individual-patient data meta-analysis provides the most comprehensive evidence to date on the duration–response relationship between ADT and outcomes when combined with definitive radiotherapy. It demonstrates meaningful oncologic benefit from ADT, especially in higher-risk disease, but also reveals diminishing returns beyond 9–12 months for many endpoints and a near-linear increase in other-cause mortality with long-term ADT. Clinicians should use a risk-adapted approach—favoring no or short-course ADT for some intermediate-risk patients and balancing prolonged ADT for high–very-high-risk patients against individual comorbidity profiles and life expectancy—while implementing strategies to mitigate noncancer harms.
Funding and clinicaltrials.gov
The pooled analysis was conducted by authors of the cited JAMA Oncology publication. Individual trials contributing data were supported by various academic and cooperative groups; trial-level funding and clinicaltrials.gov identifiers are detailed in the original publication (Zaorsky et al., JAMA Oncol. 2025).
References
1. Zaorsky NG, Sun Y, Nabid A, et al. Optimal Duration of Androgen Deprivation Therapy With Definitive Radiotherapy for Localized Prostate Cancer: A Meta-Analysis. JAMA Oncol. 2025 Nov 20:e254800. doi:10.1001/jamaoncol.2025.4800.
2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. 2024 (latest available version).
3. European Association of Urology. EAU Guidelines on Prostate Cancer. 2024 (latest available version).
4. Bolla M, van Poppel H, Collette L, et al. Improved survival with radiotherapy plus long-term androgen suppression in localized prostate cancer (EORTC 22863). N Engl J Med. 1997;337(5):295–300. (Landmark trial establishing benefit of combined treatment.)
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A middle-aged man in a clinic gown sits at a consultation desk with a radiation oncologist; a wall poster behind them shows a prostate diagram and a horizontal timeline labeled ‘ADT duration 0–36 months’ with green (benefit) and red (risk) icons. The scene is professional, calm, and informative with warm lighting.
