Improving treatment of prostate cancer is critically relevant to Veterans' health. Prostate cancer is diagnosed in more than 12,000 American Veterans annually and accounts for one third of all cancer diagnoses in American male Veterans. It is the second leading cause of cancer death in American male Veterans. Metastatic prostate cancer is incurable and treatment is palliative. The current standard of care is ADT (androgen deprivation therapy); however, relapse is inevitable. Improved treatment strategies are needed. Fortuitously, a recent confluence of diagnostic and treatment advances now raises the question if a multimodal approach with aggressive, early treatment of newly diagnosed metastatic prostate cancer could be attempted with curative intent in some patients. These advances include improved staging scans, proven benefits to early initiation of docetaxel in patients with hormone sensitive disease, improvements in androgen suppressive therapies (e.g., abiraterone acetate and apalutamide), and demonstration that stereotactic body radiotherapy (SBRT) can offer control of metastatic sites in excess of 95%. We believe that these recent advances can and should be leveraged to improve treatment efficacy for Veterans diagnosed with metastatic prostate cancer. Retrospective data from our institution show that the outcomes of Veterans with newly diagnosed prostate cancer limited to 1-5 sites of metastases (i.e., ?oligometastases?) are superior to those of Veterans with greater than 5 sites of metastasis, which has led our team to select patients with newly diagnosed metastatic prostate cancer with 5 or fewer visible metastases for inclusion in a prospective Phase II clinical trial. We propose a single arm Phase II clinical trial in patients with newly diagnosed M1a,b prostate cancer and 1-5 radiographically visible metastases staged by NaF PET-CT. In this trial, patients are treated with radical prostatectomy (and post-operative fractionated radiotherapy for pT?3a, pN1, and positive margins), metastasis directed SBRT, six cycles of docetaxel, and complete ADT with GnRH analog leuprolide, abiraterone acetate, and apalutamide for a total of six months of systemic therapy. The primary endpoint is the percent of patients achieving a PSA <0.05 ng/mL six months after recovery of testosterone to ?150 ng/dL, which is a surrogate for disease control. Prior to enrollment, patients undergo a radiographic directed biopsy of a metastatic lesion to confirm metastatic disease and obtain metastatic tumor tissue for correlative studies. This trial will yield evaluable tissue (metastatic lesions through biopsy and the primary malignant prostate by prostatectomy) from previously untreated prostate cancer patients with metastatic disease. Using this tissue, we will identify the primary tumor in each patient that gave rise to the biopsied metastasis, and compare these potentially lethal, ?true? primaries with the other intraprostatic tumors that likely did not yield metastases. We will also compare these potentially lethal primary tumors to their corresponding metastases. In doing so, we will (1) identify characteristic features of potentially lethal primary prostate tumors that are destined for metastasis, and (2) identify which pathways become activated within these potentially lethal primary tumors during or after the metastatic event. These investigations will utilize comparative genomic hybridization, RNA-sequencing, and exome-sequencing from the metastases and intraprostatic tumors. This correlative analysis is unique because all prior genomic comparisons of metastatic vs primary prostate tumors evaluated metastases from heavily pre-treated patients and compared them to primary tumors from the TCGA, which is comprised of both indolent and aggressive primary tumors. (This approach obscures identification of the initial drivers of metastases.) Therefore, our trial offers a unique window of opportunity to study the genomic drivers of lethal and metastatic prostate cancer. In this proposal, we will conduct this Phase II clinical trial (Aim 1) and the correlative analyses (Aim 2).
Improving treatment of prostate cancer is critically relevant to Veterans' health. Prostate cancer is diagnosed in approximately 12,000 American Veterans annually and accounts for one third of all cancer diagnoses in American male Veterans. It is the second leading cause of cancer death in American male Veterans. Metastatic prostate cancer is incurable and the treatment approach is palliative. The current standard of care is ADT (androgen deprivation therapy); however, relapse on ADT is inevitable. Clearly, improved treatment strategies for Veterans with metastatic prostate cancer are needed. We propose a single arm Phase II clinical trial in patients with newly diagnosed metastatic prostate cancer. This trial incorporates surgery, radiotherapy, chemotherapy, and hormonal therapy. In this proposal, we will conduct this Phase II clinical trial and conduct correlative analyses aimed at understanding the biology of metastatic prostate cancer and how we can better treat it.