Highlight
- Systemic treatment intensification (TI) with androgen receptor pathway inhibitors (ARPIs) and/or chemotherapy significantly improves overall survival (OS) in metastatic hormone-sensitive prostate cancer (mHSPC).
- Age modifies the OS benefit: younger men (<70 years) derive greater survival advantage than older men (≥70 years).
- In older men, especially those receiving triplet therapies or with low-volume synchronous disease, OS benefits from TI are less pronounced or absent.
- Findings provide critical insights for personalized treatment strategies in older men, emphasizing careful consideration of disease burden and intensity of therapy.
Study Background
Prostate cancer remains a leading cause of cancer-related mortality worldwide and metastatic hormone-sensitive prostate cancer (mHSPC) represents a critical clinical stage with high morbidity and mortality. Treatment intensification (TI) strategies incorporating androgen receptor pathway inhibitors (ARPIs) and chemotherapy have markedly improved outcomes compared to androgen deprivation therapy (ADT) alone. However, treatment decisions often consider patient age because older men with mHSPC frequently have comorbidities and higher risks of competing mortality, potentially limiting the efficacy and tolerability of intensive systemic regimens.
Understanding how age influences the survival benefit from treatment intensification has important clinical implications. This study aimed to rigorously evaluate whether age modifies the overall survival benefit associated with intensified systemic therapy in mHSPC, utilizing comprehensive aggregate data and individual patient data (IPD) meta-analyses.
Study Design
A systematic literature search spanning MEDLINE, Embase, and major oncology conference proceedings identified randomized phase 3 trials of systemic TI in mHSPC published between January 2010 and January 2024. The analysis incorporated 11 randomized comparisons involving 13,648 patients, classifying patients primarily by age dichotomized at 70 years (except one trial using 75 years).
Systemic TI included the addition of ARPIs and/or chemotherapy to standard ADT. To validate findings, individual patient data from three major trials—TITAN, ARASENS, and LATITUDE—were analyzed. Meta-analyses used random-effects models, and meta-regression was conducted via Hartung-Knapp methods to explore interaction effects between age and treatment intensity on OS.
Key Findings
Across the pooled data, treatment intensification was associated with a statistically significant improvement in overall survival (hazard ratio [HR] 0.73; 95% confidence interval [CI], 0.68–0.78). However, this benefit was modified by age (P-interaction <0.001):
- Younger men (<70 years) had a more robust OS benefit (HR 0.63; 95% CI, 0.56–0.70).
- Older men (≥70 years) experienced a more modest but still significant benefit (HR 0.82; 95% CI, 0.74–0.90).
Notably, in trials predominantly evaluating triplet therapy (ADT plus ARPI plus chemotherapy), older men did not have a statistically significant OS benefit (HR 0.94; 95% CI, 0.77–1.14), suggesting limited incremental survival advantage with intensified regimens in this subgroup.
The individual patient data meta-analysis corroborated these results. Subgroup analyses revealed that among older men with high-volume synchronous metastatic disease, ARPI addition conferred improved OS (HR 0.83; 95% CI, 0.70–0.99). In contrast, in older men with low-volume synchronous disease, no clear OS improvement was observed with ARPI addition (HR 0.89; 95% CI, 0.61–1.30).
These data suggest that both age and disease burden are critical determinants of TI efficacy, with diminished returns for older patients particularly in lower disease volume contexts where local therapy such as radiotherapy remains standard.
Expert Commentary
The findings present a nuanced view of treatment selection in mHSPC, balancing the benefits of therapy intensification with patient age and disease characteristics. Current clinical guidelines emphasize intensified systemic therapy early in disease for suitable patients but often do not stratify recommendations finely by age or comorbidity.
This study highlights the need for individualized treatment planning and reinforces that older patients, who may be frailer or have competing health risks, require tailored consideration. The absence of significant OS benefit with triplet therapy in older men prompts clinicians to weigh toxicity and quality of life more heavily. Moreover, the lack of benefit in older men with low-volume synchronous disease supports continuing primary site radiotherapy per standard care without routine systemic intensification.
Limitations include heterogeneity in age cutoffs across trials and potential underrepresentation of the very elderly or those with significant comorbidities. Real-world studies will be valuable to confirm applicability beyond clinical trial populations.
Conclusion
This comprehensive meta-analysis establishes that systemic treatment intensification significantly improves survival in men with metastatic hormone-sensitive prostate cancer, with the degree of benefit influenced by age and tumor burden. Younger men derive substantial survival gains, whereas older men, particularly those with low-volume disease or receiving triplet therapy, benefit less or not at all.
These findings inform clinical decision-making, guiding appropriate use of intensified systemic therapies while mitigating overtreatment in older patients who have greater competing risks and potential treatment toxicity. Future research should focus on optimizing risk stratification, incorporating geriatric assessment, and integrating systemic therapy with local treatment modalities to maximize outcomes across age groups.
Funding and ClinicalTrials.gov
The study was funded by the National Institutes of Health and other collaborators. Included trials such as TITAN, ARASENS, and LATITUDE are registered on ClinicalTrials.gov.
References
- Morgans AK, Roy S, Jia AY, et al. Age and Treatment Intensification in Metastatic Hormone-Sensitive Prostate Cancer. NEJM Evid. 2025 Nov;4(11):EVIDoa2500109. doi:10.1056/EVIDoa2500109.
- Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J Med. 2015 Aug 20;373(8):737-46. doi:10.1056/NEJMoa1503747.
- James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomized controlled trial. Lancet. 2016 Oct 8;387(10024):1163-1177. doi:10.1016/S0140-6736(16)00561-9.
- Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 2019 Apr 25;380(21): 1078-1088. doi:10.1056/NEJMoa1811708.
- Smith MR, Saad F, Chowdhury S, et al. Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. N Engl J Med. 2018 Jan 11;378(15):1408-1418. doi:10.1056/NEJMoa1715546.
