Neoadjuvant strategies in locally advanced prostate cancer: progress or premature?

Current European Association of Urology guidelines recommend radical prostatectomy as part of multimodal treatment for patients with high-risk, locally advanced prostate cancer (weak recommendation) (1). The optimal treatment strategy of this advanced disease stage represents a major challenge owing to the lack of high-quality trial date in the field (1,2). Therefore, in the phase 2 randomized study, Qian et al. set the ambitious goal of comparing neoadjuvant chemohormonal with neoadjuvant androgen deprivation therapy (ADT) (3). A total of 141 patients with locally advanced, high-risk prostate cancer without metastases on conventional imaging were randomized in 2:1 ratio to 6 cycles of neoadjuvant docetaxel + ADT or neoadjuvant ADT alone for 24 weeks in a prospective setting.

The study met its primary endpoint, patients treated with neoadjuvant chemohormonal therapy had significantly better 3-year (29% vs. 9.5%, P=0.002) and median (17 vs. 14 months) biochemical progression-free survival (bPFS) compared to neoadjuvant ADT alone (median follow-up 53 months) (3). However, no statistically significant difference was found in terms of pathological response (65% vs. 48%, P=0.06) and minimal residual disease (8.4% vs. 2.4%) rates (3). Despite the obvious strengths of the study such as its prospective design, rigorous methodology and follow-up of patients, it exhibits significant limitations as well.

First, owing to the short follow-up time, overall survival (OS) as well as its only validated intermediate clinical endpoint, metastasis-free survival (MFS) could not be assessed (4). Considering that bPFS is a weak surrogate endpoint of OS in this setting, the benefit of neoadjuvant chemohormonal therapy over ADT should be interpreted with caution (4). Interestingly, despite the study met its primary endpoint, no statistically significant difference was observed in any of the pathological secondary endpoints, a possible explanation for that is the lack of adequate sample size for these outcomes.

Another major limitation of the trial is the use of conventional imaging for staging of the disease, which makes the interpretation of the results questionable in the current diagnostic and treatment landscape, where prostate-specific membrane antigen (PSMA) molecular imaging is becoming the standard of care (1). Notably, a significant proportion of study participants would have been metastatic on new-generation imaging, who could benefit from treatment intensification with chemotherapy. Moreover, with the growing utility of androgen receptor pathway inhibitor-based combinations (ARPI) in advanced disease stages, comparative trials would be needed to find the optimal place of docetaxel-based neoadjuvant therapy in the treatment landscape, especially as they exhibit a generally worse side effect profile compared to ARPI, significantly hampering life quality. Notably, 28% of the patients receiving docetaxel and ADT experienced grade ≥3 adverse events and no data on quality of life was reported (3).

Third, a prospective head-to-head comparison of this neoadjuvant surgical approach to radiation-based trimodality approach should be considered.

In conclusion, the study by Qian et al. underscores the potential of neoadjuvant chemohormonal treatment in the high-risk, locally advanced disease setting. However, its adoption into routine clinical practice should be tempered with caution, carefully considering the benefits in bPFS against the absence of OS or MFS improvements, high toxicity and lack of quality-of-life data. Patient-tailored approaches, integrating tumor genetic data and biomarkers could optimize patient selection for neoadjuvant chemohormonal treatment in the future. Furthermore, the development of biomarkers to identify patients who might benefit from this approach is crucial.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Andrology and Urology. The article has undergone external peer review.

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-77/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-77/coif). I.H. reports that she received consulting fees, honoraria and travel support from Astellas, Bayer, Janssen, Pfizer, Amgen, Novartis, MSD, Sandoz, Astra Zeneca, and Eurobio. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Cornford P, van den Bergh RCN, Briers E, et al. EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guidelines on Prostate Cancer-2024 Update. Part I: Screening, Diagnosis, and Local Treatment with Curative Intent. Eur Urol 2024;86:148-63. [Crossref] [PubMed]
2. Devos G, Devlies W, De Meerleer G, et al. Neoadjuvant hormonal therapy before radical prostatectomy in high-risk prostate cancer. Nat Rev Urol 2021;18:739-62. [Crossref] [PubMed]
3. Qian H, Chi C, Tricard T, et al. A Prospective Randomized Trial of Neoadjuvant Chemohormonal Therapy vs Hormonal Therapy in Locally Advanced Prostate Cancer Treated by Radical Prostatectomy. J Urol 2024;211:648-55. [Crossref] [PubMed]
4. Miszczyk M, Rajwa P, Fazekas T, et al. The State of Intermediate Clinical Endpoints as Surrogates for Overall Survival in Prostate Cancer in 2024. Eur Urol Oncol 2024;7:1195-8. [Crossref] [PubMed]