Localized high-risk (HR) prostate cancer (PCa) presents a significant challenge due to the increased likelihood of biochemical recurrence, metastatic progression, and cancer-related mortality. Recent studies and ongoing clinical trials are exploring neoadjuvant therapies before radical prostatectomy (RP) to improve surgical outcomes and long-term survival rates. While conventional androgen deprivation therapy (ADT) has shown promise in reducing tumor volume and positive surgical margins, it has not demonstrated survival advantages. Novel agents, such as androgen receptor-targeted agents (ARTAs), have shown significant survival benefits in metastatic castration-resistant PCa, prompting investigation in the neoadjuvant setting.
Current Guideline Recommendations
Currently, international guidelines do not recommend neoadjuvant therapy with ADT before RP as a standard clinical practice. The National Comprehensive Cancer Network (NCCN) guidelines strongly discourage the use of ADT as a neoadjuvant therapy outside of clinical trials due to a lack of evidence regarding survival outcomes. The European Association of Urology (EAU) guidelines also do not recommend neoadjuvant ADT prior to RP as standard clinical practice.
Neoadjuvant Chemotherapy Trials
While ADT before surgery has shown histological benefits without significant improvements in biochemical progression-free survival, studies with Docetaxel have shown increased median overall survival in metastatic castration-resistant PCa. The CALGB (Alliance) group conducted a study randomizing 788 patients with clinically localized, HR PCa into neoadjuvant chemohormonal therapy (CHT) or RP alone. While 3-year and 5-year biochemical-PFS and PCa Cancer-Specific Mortality showed no significant differences, overall BPFS, MFS and OS were superior in the neoadjuvant arm.
Neoadjuvant ADT and ARTAs
With the advent of ARTAs, the management of HR PCa has evolved, but evidence supporting their use as neoadjuvant therapy before RP remains limited. Several phase I and II trials are evaluating different strategies for ADT and ARTAs in the neoadjuvant setting. Taplin et al. conducted two phase II RCTs comparing Enzalutamide + Abiraterone + Prednisone + ADT (ELAP) to Enzalutamide + ADT (EL), and Apalutamide + Abiraterone + Prednisone + Leuprolide (AAPL) with Abiraterone + Prednisone + Leuprolide (APL). The ELAP trial reported a favorable pathologic complete response (pCR) trend, while the AAPL trial showed similar pCR and minimal residual disease (MRD) rates compared to APL.
Fleshner et al. led a phase II RCT in patients with D’Amico HR localized PCa treated with neoadjuvant Abiraterone + Leuprolide with or without Cabazitaxel. The pCR/MRD rates were similar in both arms, but patients with pCR/MRD had superior 12-month BRFS. Schweizer et al. conducted a single-arm phase II trial with HR or very high-risk (VHR) PCa treated with Abiraterone + Apalutamide + Degarelix + Leuprolide + Indomethacin, showing a 5% pCR rate and 30% MRB rate.
Lee et al. conducted a phase II trial using Apalutamide as a neoadjuvant monotherapy, observing reduced AR activity in pre-treatment biopsies of biochemical non-responders and upregulated innate immune-related pathways. The ARNEO trial, a double-blind, placebo-controlled trial, evaluates Degarelix +/- Apalutamide as neoadjuvant therapy, showing improved metastatic disease-free survival with Degarelix + Apalutamide compared to Degarelix alone. The PROTEUS trial (NCT03767244), a large phase III study, aims to determine if Apalutamide + ADT before and after RP is superior to placebo + ADT.
Neoadjuvant Treatment with Lu-177
Lutetium-177-PSMA is being explored in clinical trials like LUNAR for oligorecurrent PCa and in neoadjuvant settings for localized PCa. Golan et al. published a safety profile study, including patients with localized HR PCa or pelvic lymph node involvement, receiving LuPSMA intravenously. The study concluded that LuPSMA administration as a neoadjuvant treatment, followed by RARP, appears safe from a surgical perspective. LuTectomy, a prospective phase I/II study, assesses Lutetium-177-PSMA-617 as a neoadjuvant therapy prior to RP, showing that it is safe and effective with high and targeted dose delivery.
Genomic Alterations and Molecular Response Markers
Trials are evaluating neoadjuvant treatments based on genomic alterations, including immunotherapies. The genomic umbrella neoadjuvant study (GUNS) is a multi-arm study assessing targeted therapies based on genomic alterations. The NePtune trial assesses neoadjuvant PARP inhibition with Olaparib in patients with HR PCa presenting BRCA 1/2 gene alterations. Studies are also investigating molecular markers to predict treatment responses, with findings suggesting that PTEN-loss and ERG + expression are associated with larger residual tumors.
Conclusions
Currently, no phase III data supports the use of systemic neoadjuvant therapies before RP. Phase II studies show promising data for ADT with second-generation agents, including favorable pCR and MRD, along with PSA relapse and salvage therapy rates. Ongoing studies should incorporate translational endpoints to identify resistance mechanisms and develop innovative biomarkers, enabling tailored neoadjuvant hormonal treatments for patients with HR PCa.
