In our recently published review, we explored the current evidence and future directions for neoadjuvant treatment in HR PCa, focusing on androgen deprivation therapy (ADT), androgen receptor pathway inhibitors (ARPIs), chemotherapy, radioligand therapies, and genomic-based strategies.
Reflections on Current Data and Trials
Despite early studies showing pathological benefits of neoadjuvant ADT, such as reduced tumor volume and fewer positive surgical margins, no significant survival benefit has been demonstrated. Consequently, major guidelines, including the EAU and NCCN, do not recommend neoadjuvant ADT outside of clinical trials.
Recent phase II trials using ARPIs have shown encouraging pathological complete response (pCR) and minimal residual disease rates. For instance, the Taplin et al. trial reported a 30% pCR rate with Enzalutamide + Abiraterone + ADT, highlighting the potential of intensified hormonal blockade.
We also found value in trials such as ARNEO, which introduced PSMA PET imaging and PTEN loss as biomarkers of response, underscoring the importance of personalized treatment approaches in this setting.
Phase III Trials: The Role of PROTEUS
One development in this field is the ongoing PROTEUS trial (NCT03767244), a phase III randomized, double-blind study evaluating apalutamide + ADT vs placebo + ADT vs RP alone as neoadjuvant and adjuvant therapy in patients with high-risk localized or locally advanced prostate cancer. The primary endpoints include pathologic complete response and metastasis-free survival. This trial represents a pivotal step toward generating level I evidence on the role of ARPIs in both pre- and post-surgical settings, potentially redefining the standard of care for HR PCa if results are positive.
We believe the PROTEUS trial and others like it are essential to establish whether neoadjuvant ARPI-based therapy can translate early pathological benefits into meaningful survival outcomes, and to clarify which patient subgroups benefit most.
Innovations and Future Directions
Among novel therapies, the LuTectomy trial evaluating 177Lu-PSMA-617 demonstrated that radioligand therapy can be safely integrated prior to RP, with promising tumor-targeted effects and minimal perioperative complications.
Additionally, genomically guided approaches, such as NePtune (Olaparib in BRCA-mutated PCa) are shaping the future of personalized neoadjuvant strategies, offering tailored treatments that may improve efficacy while minimizing unnecessary toxicity.
Conclusion
Currently, no phase III trial has conclusively established the benefit of neoadjuvant therapy before RP, but phase II data, particularly those involving second-generation agents like ARPIs, are promising. The future of this approach lies in precision medicine, using molecular markers, imaging, and PSA kinetics to identify ideal candidates, optimize timing, and avoid delays in definitive treatment.
Written by:
- Juan Gómez Rivas, MD, FEBU, PhD, Department of Urology, Hospital Clínico San Carlos, Madrid, Spain
- Jesús Moreno Sierra, Department of Urology, Hospital Clínico San Carlos, Madrid, Spain