Highlight
This large retrospective study of veterans with de novo metastatic hormone-sensitive prostate cancer (mHSPC) demonstrates a rising adoption of combination therapies, associated with improved overall survival (OS) compared with androgen deprivation therapy (ADT) monotherapy. Among those receiving doublet therapy, androgen receptor pathway inhibitors (ARPIs) and docetaxel showed similar OS across both high- and low-volume disease, but ARPIs were linked to longer progression-free survival (PFS), highlighting the need for further research to clarify the optimal treatment choice, especially regarding chemotherapy’s role.
Study Background
Metastatic hormone-sensitive prostate cancer (mHSPC) represents an advanced stage of prostate cancer in which the disease has spread beyond the prostate but remains responsive to androgen deprivation therapy (ADT). Traditionally, ADT monotherapy was the cornerstone of treatment. However, clinical trials over the past decade have established combination regimens incorporating docetaxel chemotherapy or newer androgen receptor pathway inhibitors (ARPIs) as superior options, improving survival outcomes. Despite evidence, real-world application patterns and comparative effectiveness data are limited, particularly in the veteran population, which often presents with unique demographic and clinical characteristics. Moreover, optimal treatment selection between ARPIs and docetaxel, particularly among high-volume disease patients, remains unresolved due to lack of direct comparative trials.
Study Design
This retrospective cross-sectional study analyzed data from 6,216 male veterans diagnosed with de novo mHSPC within the US Veterans Health Administration from January 2013 through December 2022. Inclusion required initiation of ADT within three months post-diagnosis. Treatment details of mHSPC combination therapy (within four months of starting ADT) were collected. Subgroups were stratified according to disease volume (high vs low), determined via radiology reports. Major endpoints were overall survival (OS) and clinical progression-free survival (PFS), operationalized as time to development of castration resistance or death. Statistical analysis covering hazard ratios (HR) and confidence intervals (CI) was performed, adjusting for patient demographics and comorbidities where applicable.
Key Findings
The study population had a mean age of 73.9 years (SD 9.7). Use of combination therapy rose markedly, from 54.0% in 2020 to 63.1% in 2022 among patients initiating ADT, indicating evolving clinical practice towards intensified treatment.
In a subset of 4,106 veterans treated from 2017 to 2022, combination therapy correlated with a significant OS benefit compared to ADT alone: 40.3 months (95% CI, 38.0-42.1) vs 33.0 months (95% CI, 31.2-35.1), with a hazard ratio of 0.80 (95% CI, 0.74-0.87). Patients receiving combination therapy tended to be younger with fewer comorbidities, reflecting possible clinician selection biases.
Among 1,174 veterans with high-volume mHSPC, no statistically significant OS difference was observed between those treated with ARPIs versus docetaxel (median OS 32.3 vs 34.7 months; HR 1.06, 95% CI 0.91-1.23). Nevertheless, ARPIs conferred longer PFS (18.7 vs 16.0 months; HR 0.80, 95% CI 0.70-0.91; P = .001). Multivariable adjustment confirmed no OS difference (adjusted HR 0.89, 95% CI 0.76-1.05).
In the low-volume disease group (366 veterans), ARPIs similarly did not improve OS compared to docetaxel (68.4 vs 55.3 months; HR 0.81, 95% CI 0.58-1.13) but significantly prolonged PFS (39.7 vs 24.0 months; HR 0.57, 95% CI 0.43-0.76).
These findings suggest that while both doublet therapies yield comparable overall survival outcomes, ARPIs may delay disease progression more effectively.
Expert Commentary
This study effectively captures evolving treatment trends in a large, real-world veteran cohort, providing crucial insights into the effectiveness of combination therapies in mHSPC. The increased use of combination regimens aligns with guideline recommendations advocating early intensification of treatment to optimize survival.
The lack of OS difference between ARPIs and docetaxel, despite improved PFS with ARPIs, underscores the complexity of therapeutic decision-making. Docetaxel remains a cost-effective, short-course chemotherapy option but has higher toxicity risks, which may affect treatment suitability. ARPIs offer oral administration and favorable toxicity profiles but bear increased cost and potential for long-term side effects. The findings call attention to individual patient factors such as age, comorbidities, and preferences, informing personalized treatment strategies.
Limitations include the retrospective design susceptible to confounding and the veteran population’s demographic specificity, which may limit generalizability. Also, granular data on quality of life, toxicity, and subsequent therapies were not reported. Further prospective head-to-head trials of ARPIs versus docetaxel in diverse populations are warranted to elucidate optimal approaches, particularly in high-volume disease.
Conclusion
This comprehensive analysis reveals increasing adoption of combination therapies in de novo mHSPC among veterans, associated with meaningful survival benefits over ADT monotherapy. ARPIs and docetaxel demonstrate comparable overall survival across disease volumes, with ARPIs providing longer progression-free intervals. These findings support current guideline-endorsed use of combination strategies but highlight ongoing uncertainty about chemotherapy’s role in the ARPI era. Clinicians should continue to individualize treatment, balancing efficacy, toxicity, and patient factors while awaiting further comparative evidence.
Future research priorities include randomized direct comparisons, real-world toxicity assessments, cost-effectiveness analyses, and exploration of biomarkers guiding therapy selection. This study lays an important foundation for evidence-based optimization of mHSPC management in veteran and broader populations.
Funding and Registration
The study was conducted within the US Veterans Health Administration infrastructure. No specific external funding or clinical trial registration information was provided.
References
1. Schoen MW, Doherty J, Eaton D, et al. Treatment Patterns and Survival Among Veterans With De Novo Metastatic Hormone-Sensitive Prostate Cancer. JAMA Netw Open. 2025 May 1;8(5):e259433. doi: 10.1001/jamanetworkopen.2025.9433.
2. James ND, Sydes MR, Clarke NW, et al. Docetaxel and/or Abiraterone for Prostate Cancer. N Engl J Med. 2016;375(2):135-146.
3. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with Standard First-Line Therapy in Prostate Cancer. N Engl J Med. 2019;381(2):121-131.
4. Fizazi K, Tran N, Fein L, et al. Abiraterone plus ADT in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J Med. 2017;377(4):352-360.
