Neoadjuvant androgen deprivation therapy with bicalutamide compared to hormonal agents in treating high-risk prostate cancer: a real-world cohort study

Introduction

Prostate cancer (PCa) remains the second most frequently diagnosed cancer and the fifth leading cause of cancer-related mortality among men worldwide (1). Approximately 15–20% of patients with PCa have high-risk or locally advanced disease at initial diagnosis (2,3), which is associated with significantly worse oncological outcomes compared to localized, low-risk PCa. Despite the application of aggressive local therapy—such as radical prostatectomy (RP) or radiotherapy (RT)—combined with prolonged adjuvant androgen deprivation therapy (ADT), more than half of high-risk patients experience biochemical recurrence (BCR) within 10 years, accounting for the majority of PCa-specific mortality (4,5).

Management of high-risk prostate cancer (HRPC) and locally advanced prostate cancer (LAPC) requires a multimodal approach. Risk stratification is based on the European Association of Urology (EAU) guidelines, which incorporated clinical stage, Gleason score (GS) or International Society of Urological Pathology (ISUP) grade group (GG), and prostate-specific antigen (PSA) level. High-risk localized disease is typically defined by at least one of the following: PSA >20 ng/mL, ISUP GG 4–5 (GS ≥8), or clinical stage ≥ cT2c. Locally advanced disease generally implies extraprostatic extension (cT3–4) and/or regional lymph node involvement (cN1) (3).

The cornerstone of treatment for patients with HRPC and LAPC involves definitive local therapy (RP or RT) combined with systemic therapy (6). Historically, standard neoadjuvant/adjuvant systemic treatment consisted of ADT, often with a first-generation antiandrogen such as bicalutamide (BICA), which aimed to reduce tumor volume, facilitate pathological downstaging, decrease positive surgical margins (PSMs), and eradicate micrometastases, thereby potentially improving surgical outcomes and long-term survival (7). Meta-analyses have confirmed that neoadjuvant ADT reduces prostate volume, PSA levels, and PSMs (8). However, this approach has consistently failed to improve progression-free survival (PFS) or overall survival (OS) (8-10). The limited efficacy of conventional neoadjuvant ADT is largely attributed to the incomplete blockade of the androgen signaling pathway. First-generation antiandrogens such as BICA can act as partial agonists, potentially activating mutant androgen receptors (ARs), and do not suppress intratumoral androgen synthesis, ultimately leading to treatment resistance (11,12). These limitations underscore the need for more potent AR pathway inhibitors in the neoadjuvant setting.

The introduction of novel hormonal therapy (NHT), also referred to as androgen receptor pathway inhibitor (ARPIs) therapy, has altered the therapeutic landscape for PCa. NHT agents include abiraterone acetate (a CYP17 inhibitor that blocks androgen synthesis) and second-generation AR antagonists such as enzalutamide, apalutamide, darolutamide, andrezvilutamide—with the latter being a developed and approved in China (13-15). These agents provide more pronounced and comprehensive suppression of the androgen axis, with well-established efficacy in both metastatic hormone-sensitive and castration-resistant PCa (16-20). Given their favorable efficacy and safety profiles, NHT agents are increasingly being investigated in the neoadjuvant setting and as components in neoadjuvant therapy. For example, the ongoing PROTEUS trial (NCT03767244) (2) is a phase III randomized study comparing apalutamide plus ADT to placebo plus ADT prior to RP. Similarly, the NCT05009290 trial (15) is evaluating neoadjuvant darolutamide plus ADT in patients with HRPC and LAPC. The results from these trials are expected to provide clinically relevant guidance for local treatment strategies.

Despite the growing interest in neoadjuvant regimens for patients with PCa, studies directly comparing conventional ADT plus BICA and ADT plus NHT agents remain scarce. Key questions persist regarding the depth of pathological response—such as pathological complete response (pCR) and minimal residual disease (MRD)—and the ultimate impact on long-term outcomes such as BCR-free survival and OS.

Therefore, this study conducted a retrospective cohort analysis comparing neoadjuvant ADT plus a first-generation antiandrogen (BICA) to ADT combined with an NHT agent (abiraterone, darolutamide, or rezvilutamide) in patients with HRPC or LAPC undergoing RP. The principal outcomes examined included pathological response metrics (pCR, MRD, pathological downstaging, and surgical margin status) and early indicators of treatment success (PSA response and time to BCR). The findings from this study may constitute real-world evidence for informing and optimizing neoadjuvant strategies in this challenging patient population. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2923/rc).

Methods

Study design

A retrospective cohort study was conducted at the Department of Urology, Peking University Cancer Hospital & Institute. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the institutional review board of Peking University Cancer Hospital & Institute (No. 2020KT85). All patients enrolled in the study provided written informed consent.

Patients diagnosed with HRPC or LAPC who received neoadjuvant therapy followed by RP between January 2020 and June 2025 were included. Participants were categorized into two groups: the conventional regimen group (ADT + BICA) and the novel regimen group (ADT + NHT; including abiraterone plus prednisone, rezvilutamide, or darolutamide). The NHT group was further subdivided stratified by specific agent for exploratory analysis.

Endpoints

The primary endpoints included pCR rate, incidence of MRD (defined as residual tumor diameter ≤5 mm) (3), pathological downstaging rate [based on American Joint Committee on Cancer eighth edition staging (21)], and PSM rate. Secondary endpoints included the rate of ≥50% decline in PSA level (PSA50 response rate), PSA90 response rate, and BCR rate (defined as serum PSA level exceeding 0.2 ng/mL on two consecutive tests, with the second measurement being ≥0.2 ng/mL) (22).

Study participants

The inclusion criteria for participants were as follows: histologically confirmed prostatic adenocarcinoma via biopsy; high-risk or locally advanced disease, with either clinical stage ≥ cT2c [confirmed by prostate-specific membrane antigen positron emission tomography-computed tomography (PSMA PET-CT)], GS ≥8, PSA level ≥20 ng/mL, or the presence of pelvic lymph node metastasis (N1); completion of at least 3 months of neoadjuvant therapy prior to RP; and availability of complete baseline and postoperative pathological data.

Meanwhile, the exclusion criteria were as follows: evidence of distant metastasis on PSMA PET-CT, prior systemic therapy for PCa (e.g., chemotherapy or immunotherapy), presence of other malignant tumors, and missing critical data (e.g., preoperative/postoperative PSA level or residual tumor rate).

Neoadjuvant therapy regimens

All patients received neoadjuvant therapy for a minimum of 3 months (median duration 4 months). The ADT regimen consisted of either goserelin (3.6 mg monthly administered subcutaneously) or leuprorelin (7.5 mg monthly administered intramuscularly). The dosing of novel agents was conducted according to the approved prescription guidelines (22).

Surgical procedure

RP was performed via robot-assisted or conventional laparoscopic techniques within 4–8 weeks after completion of neoadjuvant therapy. All surgeries were conducted by at least two senior urologists, each with an annual surgical volume of >100 cases.

Data collection and quality control

Data were extracted from the hospital’s electronic medical record system. A double-data entry method was applied, and discrepancies were resolved through consultation with a third investigator.

Statistical analysis

Continuous variables are expressed as the mean ± standard deviation, and differences between groups were evaluated with the independent samples t-test. Categorical variables are expressed as frequencies and percentages, with between-group comparisons performed with the Pearson chi-squared test or Fisher exact test, as appropriate.

Univariate and multivariate logistic regression models were used to identify independent predictors of pCR and MRD. Variables with P value <0.1 in the univariate analysis were included in the multivariate model.

Time-to-event outcomes (e.g., BCR-free survival) were analyzed via the Kaplan-Meier method, and group comparisons were conducted with the log-rank test. The number of patients at risk in each group is displayed at specified time points.

All statistical analyses were conducted with R (The R Foundation for Statistical Computing, Vienna, Austria) and GraphPad Prism software version 10.0 (Dotmatics, Boston, MA, USA). A two-sided P value <0.05 was considered statistically significant.

Results

Baseline characteristics

A total of 87 patients were enrolled: 35 (40.2%) in the ADT + BICA group and 52 (59.8%) in the ADT + NHT group. None of the patients enrolled in the study had radiologic evidence of lymph node or distant metastasis prior to surgery. The baseline characteristics, including age, body mass index (BMI), ISUP grade, initial PSA level, and lower urinary tract symptom (LUTS) incidence were comparable between the groups (Table 1).

Regarding clinical T stage, the ADT + BICA group exhibited a higher proportion of cT2 disease, while conversely, the ADT + NHT group had a higher proportion of cT3–4 cases. However, this distribution difference did not reach statistical significance (P=0.058).

Treatment response

Both groups demonstrated excellent PSA response. PSA50 was observed in all patients, and the PSA90 rate was similarly high (ADT + BICA: 97.1%; ADT + NHT: 94.2%) (Figure 1).

Figure 1 Distribution of PSA levels at the baseline, preoperative, and postoperative timepoints. PSA, prostate-specific antigen; tPSA, total prostate-specific antigen.

Pathological outcomes

Neoadjuvant NHT, compared to ADT + BICA, resulted in significantly higher pCR (15.4% vs. 0%; P=0.04) and MRD rates (30.8% vs. 8.6%; P=0.01) (Table 2, Figure 2). Pathological downstaging was also more frequent in the NHT group (44.2% vs. 22.9%; P=0.04) (Figure 3).

Figure 2 pCR and MRD in the subgroups. MRD, minimal residual disease; pCR, pathological complete response.

Figure 3 Sankey diagram for pathological downstaging. MRD, minimal residual disease; pCR, pathological complete response.

Surgical and oncological outcomes

The PSM rate was higher in the ADT + BICA group (48.6%, 17/35) than in the ADT + NHT group (32.7%, 17/52), but this difference was not statistically significant (P=0.14). Univariate analysis indicated that BMI might be a predictor of PSM. Furthermore, multivariate analysis identified T stage as an independent predictor of PSM, underscoring the influence of surgical technique and anatomical factors.

During follow-up, BCR occurred in 23.1% of patients treated with NHT and 34.3% of those treated with BICA (P=0.25). Kaplan-Meier survival analysis indicated no significant difference in BCR-free survival between groups (P=0.90) (Figure 4).

Figure 4 BCR-free survival. ADT, androgen deprivation therapy; BCR, biochemical recurrence; BICA, bicalutamide; NHT, novel hormonal therapy.

Safety

All regimens were well tolerated, and no grade 3–4 adverse events occurred. One patient (3.3%) experienced a grade 2 allergic reaction. The most common AEs, observed in nine patients (10%), were hot flashes and elevated alanine transaminase and/or aspartate transaminase levels, all of which improved with treatment and did not impact RP. All patients underwent RP successfully, with no unexpected surgical or medical complications or delays. No treatment-related deaths or surgical delays were reported.

Discussion

This real-world study demonstrated that neoadjuvant ADT + NHT can achieve significantly greater pathological response as compared to a conventional regimen of ADT + BICA in patients with LRPC or LAPC.

Notably, a significantly higher rate of pCR was achieved in the ADT + NHT group (15.4%) than in the ADT + BICA group (0%); more importantly, the rate of MRD was also found to be significantly higher in the ADT + NHT group (30.8% vs. 8.6%). Within the NHT group, darolutamide plus ADT yielded the highest rates of pCR and MRD (40%) and the lowest incidence of BCR (20.0%), in line with previous phase II studies (23-26). Taplin et al. reported a combined pCR + MDR in patients treated with 6 months of Abiraterone (ABI) + ADT (23%) as compared to those treated with 3 months of ADT alone followed by 3 months of ABI + ADT (3.6%) (13). More recently, the results from the ARNEO trial led by Devos et al. were published (27). This was a phase II randomized controlled trial assessing the efficacy of a 3-month neoadjuvant degarelix with or without apalutamide (APA) prior to RP in 89 patients with high-risk clinically nonmetastatic PCa. There was better pathologic response in terms of MRD in patients treated with APA+ ADT (38%) than in those treated with ADT alone (9%). This strongly suggests that through a more comprehensive blockade of the AR signaling pathway or suppression of androgen synthesis (16), NHT agents are capable of inducing a more pronounced level of tumor regression in the neoadjuvant setting, which is consistent with their pharmacological rationale (16,23,24).

Importantly, however, there was no significant difference in medium-term BCR-free survival between the groups (P=0.90) in our study despite the clear pathological advantage observed in the ADT + NHT group. This result is consistent with the findings from a few earlier studies and prompts a re-evaluation of the primary objectives of neoadjuvant therapy in this high-risk population (26,27).

In summary, the dissociation between significant pathological improvement and the lack of a corresponding survival benefit underscores the profound complexity of PCa biology. This malignancy should be conceptualized not as a mere localized mass, but as a complex ecosystem of heterogenous cellular clones. NHT effectively eradicates the dominant, androgen-sensitive clones, accounting for the superior rates of pCR and MRD observed in surgical specimens. However, this therapeutic pressure concurrently enriches pre-existing resistant clones—harboring genetic aberrations such as AR-V7 splice variants, PTEN loss, or TP53 mutations—through a process of Darwinian selection. Often disseminated as micrometastases prior to treatment, these resistant clones subsequently emerge as the primary drivers of post-surgical recurrence.

Critically, the micrometastases harboring these resilient clones function as formidable “fortresses”, conferring resistance to systemic therapy. This resilience is rooted in a protective niche: first, an immunosuppressive “desert” that blunts anti-tumor immunity; second, metabolic stresses (e.g., hypoxia, acidity) that select for clones adapted to harsh conditions and inherently therapy-resistant; and finally, aberrant vasculature that creates heterogeneous drug delivery and “blind spots”. Consequently, even if ARPIs reach the site, achieving a cytotoxic concentration throughout these sanctuaries remains a formidable challenge. Ultimately, it is the synergy between clonal evolution within the tumor and the protective sanctuary provided by the micrometastatic niche that prevents a deep pathological response from translating into a definitive survival advantage.

This study demonstrates that while the ADT + NHT regimen achieved significantly deeper pathological responses compared to ADT + BICA, this did not translate into a meaningfully lower rate of BCR. Notably, baseline characteristics revealed that patients in the ADT + NHT group tended to present with features associated with higher biological risk—including a greater proportion of ISUP grade 5 disease and more advanced T stage (T3/T4)—and were subsequently more likely to receive adjuvant therapy after surgery (43.2% vs. 31.4%). This clinical pattern suggests a potential selection bias, whereby clinicians may have preferentially opted for intensified neoadjuvant therapy for patients with more aggressive disease phenotypes at presentation. Thus, the observed pathological superiority in the ADT + NHT group may partly reflect the regimen’s efficacy in counterbalancing a comparatively less favorable baseline risk profile. Moreover, the higher utilization of adjuvant therapy in this same group indicates that clinicians continued to treat these patients more aggressively postoperatively, likely in response to their perceived underlying high-risk biology. Together, the sequential application of a “more potent neoadjuvant therapy” followed by “more frequent adjuvant intervention” may have operated synergistically to neutralize initial risk disparities, ultimately leading to comparable long-term disease control between the two treatment cohorts.

This balancing effect narrows the BCR disparity that would otherwise emerge, offsetting the apparent advantage of NHT. Therefore, BCR can be considered an intermediate endpoint, whereas OS remains the gold standard. Short follow-up durations may fail to capture long-term survival differences arising from pathological benefits. Although pCR and MRD are considered valuable surrogate endpoints, they primarily reflect local tumor response and may not correlate with systemic control of micrometastases in the context of tumor heterogeneity. These factors collectively highlight the critical distinction between local control and systemic disease management in PCa treatment. Future research should focus on developing more effective systemic treatment strategies while establishing a biomarker system capable of accurately reflecting overall disease control.

Another notable observation was that the PSM rate in the NHT group was lower than that in the BICA group (32.7% vs. 48.6%), although this difference did not reach statistical significance (P=0.14). Tumor downstaging is considered to potentially reduce surgical complexity and create conditions for more radical resection. However, it is worth noting that this superior pathological response was not accompanied by a statistically significant improvement in PSM rates. This discrepancy may be attributed to several factors: fibrosis or tissue reactions induced by neoadjuvant therapy may obscure surgical planes, thereby increasing the challenge of precise dissection. Furthermore, tumor regression is often heterogeneous, and residual microscopic disease at the original tumor margins might still be present at the resection edge. Finally, the sample size in this study might have been insufficient for detecting a potentially modest yet clinically relevant difference in PSM rates. This observed disconnect between the degree of pathological response and surgical margin status suggests that advancements in surgical technique [e.g., multiparametric magnetic resonance imaging (mpMRI)-guided precision planning] are as crucial as effective systemic therapy.

Among the NHT agents evaluated, darolutamide demonstrated a modestly favorable overall performance. This finding carries significant clinical implications. The unique molecular structure of darolutamide is associated with low blood-brain barrier penetration, which may contribute to a more favorable tolerability profile and a reduced incidence of central nervous system-related adverse events, potentially enhancing treatment adherence and quality of life.

Study limitations

Several limitations to this study should be acknowledged. First, as we employed a retrospective design, potential selection bias and unmeasured confounding factors could have arisen despite the general balance observed in baseline characteristics. Second, the sample was somewhat modest in size and the follow-up duration relatively short, potentially limiting the power to detect differences in the longer-term survival endpoints. Finally, given the single-center design, external validation in multicenter cohorts is needed to confirm the generalizability of the findings.

Conclusions

This real-world study provides evidence that a neoadjuvant ADT + NHT regimen induces a significantly greater pathological response as compared to conventional ADT + BICA in patients with LRPC/LAPC. Darolutamide showed particularly promising results, with the highest pathological response rate and lowest BCR rate. However, this pathological superiority did not translate into improved surgical margin outcomes or short-term survival benefits in this analysis. These findings underscore the multifaceted nature of treating high-risk PCa and highlight the necessity for longer-term follow-up to assess ultimate survival outcomes. Investigating response-guided adjuvant therapy, based on the pathological response to neoadjuvant treatment, may be a promising direction for future research. The potential suggested by darolutamide in this cohort warrants further investigation in dedicated prospective trials.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2923/rc

Data Sharing Statement: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2923/dss

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2923/prf

Funding: This study was supported the Beijing Hospitals Authority’s Ascent Plan (No. DFL20241101).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2923/coif). The 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. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the institutional review board of Peking University Cancer Hospital & Institute (No. 2020KT85), and all patients enrolled in the study provided written informed consent.

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/.

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