Although this is not what is customarily seen with cancer treatments, it may be a characteristic of modern immune therapeutics [28]. An emerging mechanism to evaluate tumor growth rates using mathematical models may provide additional insight into this phenomenon [29, 30]. In a recent review of 5 NCI mCRPC trials including a vaccine trial, there appeared to be a sustained decrease in tumor growth rate in vaccine patients 18 Short Title: Enzalutamide Vaccine in mCRPC Version Date: 03/29/2022 as compared to those treated with chemotherapy, who had transient reductions in tumor size, but then growth rate resumed at the same pre-treatment rate once cytotoxic therapy was discontinued. [31] This data suggests that a vaccine induced immune response may not decrease tumor size (or change TTP) but may lead to altered tumor growth rates which could have more substantial impact on overall survival [32]. (See Figure 8). Furthermore, unpublished data from an ECOG PSA-TRICOM trial in non-metastatic prostate cancer demonstrated a reduced growth rate within 100 days of vaccine initiation [33]. Similarly, Sipuleucel-T has significantly prolonged PSA doubling time (another way to measure growth) after initial hormonal therapy in the same patient population [31]. Together, these data suggest that for patients getting combination therapy, disease can be controlled by standard therapies in the short term, while vaccines may impact tumor growth rates in the long term, ultimately resulting in prolonged TTP compared to standard therapy alone. (Figure 8) If vaccines can alter growth rates and if cytoreductive therapies can reduce tumor burden, it would be reasonable to presume that vaccine combination therapies would potentially result in a TTP benefit. Figure 8. Vaccine as part of combination therapy may improve TTP. Although vaccine as monotherapy may have no impact on short-term TTP, vaccine in combination regimens may improve TTP by altering the rate of regrowth as the effects of the companion therapy begin to diminish. If the companion therapy is cytoreductive, tumor volume will decrease, but as the therapeutic benefits wane, regrowth will occur. If sufficient time has passed to generate an immune response, the anti-tumor effects of the immune system may result in a delay in TTP (due to a slower re-growth rate) relative to cytoreductive treatment alone. [13] 1.3 SUMMARY OF RATIONALE 1) Enzalutamide is a well-tolerated, modern androgen receptor antagonist. Phase III trial have demonstrated a 4.8 month improvement in survival in mCRPC patients who were previously treated with docetaxel. 2) PROSTVAC™ is a novel candidate for prostate cancer immunotherapy. In a randomized controlled Phase 2 trial, PROSTVAC therapy was associated with a prolongation of survival by 8.5 months in men with metastatic castrate-resistant prostate cancer. The Phase 3 efficacy trial is on-going. 3) Preclinical data has demonstrated that hormonal therapies such as ARAs can enhance the immune response through multiple mechanisms. Specifically, the LTIB has shown that enzalutamide can increase thymic production of naïve T-cells, which could be activated by a cancer vaccine. 4) Data from the clinical trials with these therapies suggest that they are very well tolerated and without overlapping toxicity. 19 Short Title: Enzalutamide Vaccine in mCRPC Version Date: 03/29/2022 5) Data suggest that for patients getting combination therapy, TTP may be a reasonable clinical endpoint and such a finding could be important in determining the ultimate clinical role of therapeutic cancer vaccines. Based on the above rationale, we will evaluate whether combining enzalutamide and PSA- TRICOM vaccine prolongs time to disease progression compared with enzalutamide alone in chemotherapy-naïve mCRPC. 2 ELIGIBILITY ASSESSMENT AND ENROLLMENT 2.1 ELIGIBILITY CRITERIA 2.1.1 Inclusion Criteria 2.1.1.1 Patients must have histologically or cytologically confirmed prostate cancer confirmed by either the Laboratory of Pathology at the NIH Clinical Center, Walter Reed National Military Medical Center at Bethesda prior to starting this study. If no pathologic specimen is available, patients may enroll with a pathologist’s report showing a histological diagnosis of prostate cancer and a clinical course consistent with the disease. 2.1.1.2 Castrate testosterone level (<50ng/dl or 1.7nmol /L) 2.1.1.3 Metastatic disease documented by one of the following: Metastatic bone disease on an imaging study, or Soft tissue disease documented by CT/MRI, or 2.1.1.4 Progressive disease at study entry defined as one or more of the following criteria occurring in the setting of castrate levels of testosterone: i. Radiographic progression defined as any new or enlarging bone lesions or growing lymph node disease, consistent with prostate cancer OR ii.