Efficacy and Mechanisms of Resistance to Neoadjuvant Intensive Androgen Signaling Inhibition

PROJECT SUMMARY – PROJECT 1 Localized high-risk prostate cancer (PCa) comprises ~15% of newly diagnosed localized PCa, and the cure rate for these tumors after primary surgical treatment by radical prostatectomy (RP) is low, with recurrent disease in up to ~50%. Neoadjuvant trials for these localized high-risk PCa may provide valuable opportunities to increase cure rates and our understanding of response and resistance. However, previous studies of neoadjuvant androgen deprivation using GnRH agonists alone have generally shown infrequent pathological complete responses (pCRs) and have not shown evidence of clinical efficacy. We have hypothesized that responses to neoadjuvant ADT have been limited due to substantial residual androgen in the prostate, and that more intensive neoadjuvant androgen signaling inhibition (ASI) therapy, in addition to increasing pCR rates, will translate into an improvement in disease free survival (DFS) and ultimately overall survival (OS). We have been testing this hypothesis in a series of phase 2 trials examining the efficacy of neoadjuvant intensive ASI using leuprolide in combination with abiraterone (ABI) and/or enzalutamide (ENZ) or apalutamide (APA) for 6 months prior to radical prostatectomy (RP). Responses appear to be improved relative to previous neoadjuvant trials, but it remains unclear whether the cases with pCR/MRD reflect tumors that have less metastatic potential. Moreover, the molecular basis for residual disease in prostate, and its relationship to metastatic disease in patients who progress, remain to be determined. To address the genomic basis of response versus resistance, we propose comprehensive genomic analyses of tumors with exceptional responses (pCR/MRD) to intensive neoadjuvant ASI therapy, and of residual disease in RP specimens in men who do not achieve pCR/MRD (Aim 1). These studies will leverage samples from our previous trials, as well as a large multicenter phase 3 study of neoadjuvant GnRH agonist/antagonist combined with APA in comparison with GnRH agonist/antagonist alone (PROTEUS trial, supported by Janssen, NCT03767244). Aim 2 will identify actionable acute nongenomic adaptations that mediate initial resistance to intensive ASI therapy, and specifically test the hypothesis that these adaptations converge on expression of D cyclins and activation of CDK4/6 to drive proliferation. Aim 3 is a randomized phase 2 trial of intensive ASI (leuprolide plus darolutamide), alone or in combination with the CDK4/6 inhibitor abemaciclib. Our long-term goal is to establish neoadjuvant trials as a platform for assessing the efficacy of novel combination therapies in castration-sensitive PCa.