McKay RR, Xie W, Ye H et al: Results of a randomized phase II trial of intense androgen deprivation therapy prior to radical prostatectomy in men with high-risk localized prostate cancer. J Urol 2021; 206: 80.

Disclosures

Rana R. McKay reports grants (institutional research funding) and personal fees (Advisory Board) from Bayer, grants from Pfizer (institutional research funding), grants from Tempus (institutional research funding), personal fees from AstraZeneca (Advisory Board), Bristol Myers Squibb (Advisory Board), Calithera (Advisory Board), personal fees from Caris (Molecular Tumor Board), personal fees from Exelixis (Advisory Board), personal fees from Janssen (Advisory Board), personal fees from Novartis (Advisory Board), personal fees from Pfizer (Advisory Board), personal fees from Sanofi (Advisory Board), personal fees from Tempus (Advisory Board), personal fees from Dendreon (Consultant) and personal fees from Vividion (Consultant) outside the submitted work.

Adam S. Kibel reports personal fees from Janssen (Advisory Board), personal fees from Bayer (Advisory Board), personal fees from BMS (DSMC), personal fees from Merck (Advisory Board), personal fees from Insightec (Advisory Board) and personal fees from Profound (Advisory Board) outside the submitted work.

Mary-Ellen Taplin reports consulting/advisory role for Janssen, Bayer, Guidepoint Global, Best Doctors, Inc., UpToDate, Clovis Oncology, Research to Practice, Myovant Sciences, Incyte, Pfizer, AstraZeneca and Arcus Ventures; travel/accommodations/expenses from Medivation, Janssen, Tokai Pharmaceuticals, Astellas Pharma, Incyte, Pfizer, Clovis Oncology and Bayer; honoraria from Janssen, Clovis Oncology, Astellas, Incyte, UpToDate, Research to Practice, Pfizer, Bayer, Amgen, AstraZenca, Progenics, Guidepoint Global, Celgene, Merck, GlaxoSmithKline, Myovant Sciences and Roivant; and research funding from Janssen, Medivation, Bayer and Pfizer.

McKay RR, Xie W, Ye H et al: Results of a Randomized Phase II Trial of Intense Androgen Deprivation Therapy prior to Radical Prostatectomy in Men with High-Risk Localized Prostate Cancer. J Urol 2021; 206: 80.

The treatment paradigm for patients with high-risk localized prostate cancer has not significantly changed in decades and includes combinations of radical prostatectomy (RP), radiation therapy and androgen deprivation therapy (ADT). Strategies to integrate systemic therapy neoadjuvant to RP have been extensively investigated and at the present time remain controversial. In the early 1990s, a series of studies investigated varying durations (3–8 months) of luteinizing hormone-releasing hormone (LHRH) agonists with or without first generation antiandrogens neoadjuvant to RP.^1,2 In aggregate, these studies were limited by small sample size, enrollment of predominantly low-risk patients, lack of randomization and central pathology review, and limited post-RP followup. While there was reduction in rates of positive surgical margins with neoadjuvant therapy, these early studies failed to demonstrate a reduction in clinical relapse and the approach was largely abandoned.

Over the last decade, with the realization that intratumoral androgen production was a common mechanism of prostate cancer progression, we and others have evaluated various combinations of next generation androgen synthesis inhibitors and androgen receptor (AR) antagonists neoadjuvant to RP.^3-6 Through a series of phase 2 trials, we have shown that 6 months of neoadjuvant therapy was better than 3 months and that, at a prostate tissue level, tumor androgens are significantly lower with combination therapy than with LHRH agonists alone. Furthermore, the combination of androgen synthesis inhibition and AR antagonism appeared to result in higher pathological responses compared to AR antagonism alone.³ Pooled analysis from a series of these neoadjuvant studies demonstrates that favorable RP pathological response correlates with freedom from prostate specific antigen (PSA) failure.^7,8

Given the prior data suggesting a potential synergistic effect of androgen synthesis inhibition and AR antagonism in patients with hormone sensitive high-risk prostate cancer, we designed a larger, multicenter, open-label, randomized phase 2 trial of abiraterone, apalutamide, leuprolide and prednisone compared to abiraterone, leuprolide and prednisone neoadjuvant to RP in patients with high-risk localized prostate cancer. The results of this study, which was designed to investigate the tissue effects of intense hormone therapy, were recently published in The Journal of Urology.⁹

The trial enrolled patients with Gleason score ≥4+3=7, PSA >20 ng/ml or T3 disease (by multiparametric magnetic resonance imaging [MRI]) and lymph node <20 mm. In Part 1, patients were randomized 1:1 to apalutamide, abiraterone acetate, prednisone and leuprolide, or abiraterone, prednisone, leuprolide and prednisone for 6 cycles (1 cycle=28 days), followed by RP. Part 2 (not reported) investigates the impact of an additional year of adjuvant therapy on 3-year biochemical progression-free survival. Surgical specimens and pre/post-treatment prostate MRI underwent central review. The primary end point for Part 1 was the rate of pathological complete response (pCR) or minimum residual disease (MRD, tumor ≤5 mm).

Figure. Representative case of a 67-year-old man with intermediate-risk disease (Gleason 4+3, PSA 8.3 ng/ml, cT2). Baseline multiparametric prostate MRI (top panel) demonstrates visible tumor on T2 weighted imaging (T2WI). He was allocated to treatment with abiraterone, prednisone and leuprolide. Following 6 months of therapy, repeat multiparameteric prostate MRI demonstrates resolution of tumor on T2WI (middle panel); however, representative images from RP specimen show invasive carcinoma on hematoxylin and eosin (H&E) staining (bottom panel). This patient had ypT3aN0 disease at RP with negative margins.

The study enrolled 119 patients from 4 institutions, of whom 118 initiated treatment and were included in the analysis. The majority of patients had high-risk prostate cancer (94%), including 71% with Gleason 8–10 disease. We demonstrate that intense neoadjuvant hormone therapy followed by RP results in favorable pathological responses (tumor <5 mm) in 21% of patients (see table). The pathological responses were similar between treatment arms, and addition of apalutamide did not result in improved response beyond that achieved with abiraterone, leuprolide and prednisone. Additionally, in the study we further refine standards for systematic central review of RP surgical specimens. We demonstrate that the neoadjuvant approach is feasible and safe, and results in minimal perioperative and postoperative complications. Furthermore, we explore imaging and tissue biomarkers of response and resistance. Central review of both post-therapy prostate MRI and RP specimens demonstrates poor concordance and correlation between MRI-assessed and pathologically assessed tumor volume (see figure). We demonstrate that PTEN loss, ERG positivity and presence of intraductal carcinoma were associated with more extensive residual tumors at RP, suggesting that patients with such features may benefit from alternative or additional treatment escalation strategies.

Our study, in addition to other contemporary neoadjuvant studies of novel hormone therapy, provides rationale for a phase 3 trial investigating perioperative ADT with or without apalutamide (NCT03767244). The study, which is expected to accrue 1,500 patients, is currently ongoing. It has a co-primary end point of pCR and metastasis-free survival. This is a landmark study that has the potential to change the treatment paradigm for patients with high-risk localized prostate cancer undergoing RP. Strategies to intensify treatment for patients at highest risk of recurrence and de-escalate therapy for those at lowest risk, sparing individuals the toxicity of treatment, have the potential to revolutionize treatment for patients with localized prostate cancer.