Project Summary / Abstract Currently, 50% of patients who have undergone post-prostatectomy radiotherapy after PSA failure manifest subsequent systemic disease. Compared to PET/CT with molecular radiotracers, conventional imaging methods fall short in identifying sites of prostate cancer recurrence. Our goal is to address an unmet public health need by improving long term biochemical control of patients with recurrent prostate carcinoma. We have verified a key scientific premise that advanced molecular imaging with the synthetic amino acid PET radiotracer fluciclovine (18F) (anti-3-[18F]FACBC) results in significantly greater disease detection, with a 40.5% change in management and 83.6% change in planning volumes (without dose escalation) compared with conventional imaging. During the course of our trial, and in large part because of our translational work, fluciclovine (18F) was FDA approved in 2016 for recurrent prostate cancer, contributing to a new standard of care. As of Version 1.2018, fluciclovine (18F) has now been included in the National Comprehensive Cancer Network (NCCN) Guidelines for restaging recurrent prostate cancer. Moreover, salvage radiotherapy is being offered at increasingly lower PSA levels, and evidence is accumulating that boosting radiotherapy dose to foci of active disease may result in clinical benefit. Preliminary analysis of still accruing data from our ongoing clinical trial (5R01CA129356: NCT01666808) suggests that integrating fluciclovine may result in a small improvement in failure rate, but not have adequate sensitivity to definitively achieve durable PSA control with standard radiotherapy doses. Yet, there is early evidence that a new class of PET radiotracer targeting the prostate specific membrane antigen (PSMA) receptor may have greater sensitivity at lower PSA levels for disease detection. Gallium-68 (68Ga) PSMA is one such PSMA PET ligand, though not FDA approved. Each class of PET radiotracer, amino acid metabolic (fluciclovine) vs receptor based (PSMA), exhibits advantages and disadvantages. Our hypothesis is that by utilizing a higher affinity PET ligand, we can better select and manage patients who will benefit from salvage radiotherapy undertaken at lower PSA levels. In addition, we hypothesize that by dose escalating targets identified with either fluciclovine (18F) or 68Ga PSMA, we will determine if dose escalation in itself provides improved PSA control. To test these hypotheses with the highest scientific rigor, we will conduct a prospective clinical trial in which patients who are eligible for salvage radiotherapy are randomized to either fluciclovine (18F) or 68Ga PSMA PET/CT. We will explore if positive specific tissue biomarker signatures may be useful to help predicts post-prostatectomy radiotherapy outcomes in combination with the standard risk criteria. Our proposal is timely since recent editorials in the literature regarding salvage radiotherapy post-prostatectomy call for integration of molecular imaging in prospective, randomized, controlled trials with toxicity analyses of the type we will carry out.

Advanced PET/CT Directed Post-Prostatectomy Radiotherapy to Enhance Prostate Cancer Outcomes Project Narrative/Relevance Our research group at Emory has current NIH support to explore advanced molecular imaging based on increased amino acid use by prostate cancer with a positron emission tomography (PET) radiotracer [fluciclovine (18F)] and compare this approach to standard imaging such as computed tomography (CT) or magnetic resonance imaging (MRI) for guiding post-surgery radiotherapy decisions and treatment planning, and for improving cancer control rates. The overall goal of the current proposal is to build on these results in patients with suspicion of recurrent or persistent prostate cancer after prostatectomy by determining if this amino acid based radiotracer [fluciclovine (18F)] or a newer PET radiotracer [68Ga PSMA] based on a specific tumor receptor called prostate specific membrane antigen can be used to better guide radiotherapy with increased doses to tumor, decide which are the best patients for this type of radiotherapy, and to see if these approaches improve prostate cancer outcomes. We will also be exploring a new direction of combining genomic information (Decipher and Sig24 signatures) with imaging results in a subset of patients to determine if this additional information may be useful to help predict post-prostatectomy radiotherapy outcomes in combination with the standard risk criteria.