Background: With genomic-based therapies approved for advanced PC, there has been a substantial rise in the clinical use of genomic sequencing. In addition to identifying actionable targets, there is a long list of less common ‘tail’ alterations in metastatic PC with unclear prognostic or predictive significance. We hypothesize that integrative clinico-genomic studies of uncommon subgroups of PC, defined based on a molecular biomarker of low-prevalence or based on an exceptional clinical outcome to therapy, can lead to the identification of new predictive and resistance biomarkers and will accelerate the development of precision medicine strategies for patients with PC. Methods: This is a multi-institutional prospective observational study for longitudinal collection of clinical and genomic data from participants (prts) with distinct molecular alterations of interest and/or exceptional phenotypes. The primary objectives are: 1) to define the natural history of men with select molecular alterations and/or exceptional clinical responses, 2) to establish a biospecimen repository for extensive molecular analyses to study the biology of PC and mediators of therapeutic response and resistance. Exploratory objectives include: 1) understanding the impact of co-occurring genomics alterations and other molecular alterations on the natural history of PC in these defined subsets, 2) identifying biologic mechanisms of exceptional response, primary and secondary resistance, and tracking evolutionary patterns that occur during acquired resistance. Eligible prts have a diagnosis of PC with known germline and/or somatic variants in PIK3A, PIK3CB, and/or AKT, PALB2, BRIP1, RAD50, RAD51, RAD54, RB1, SPOP, Wnt/B-catenin pathway, MMR genes (MLH1, MSH2, MSH6, PMS2), EPCAM and/or TMB-high (as defined by TMB ≥ 10 mut/Mb). Any platform for genomic testing is acceptable and data is collected centrally. Prts deemed exceptional responders (with or without mutational aberrations) are defined as those with a complete response or a confirmed partial response of any duration of time to systemic therapies or any response of exceptional duration (particularly with therapies targeting PARP, the androgen receptor, and/or immunotherapies). Data including demographic, disease characteristics, treatment outcomes including response to therapies, and survival are collected along with other pathologic, radiographic, and molecular/genomic data. Correlative sample collection includes archival primary and metastatic biopsy specimens and prospective collection of blood for future analyses. This study will provide insights into the significance of individual and co-occurring alterations and will help establish a path forward for the expansion of drug indications for PC patients with rare variants. 37 prts have been accrued with an accrual ceiling of 2000 prts. Clinical trial information: NCT04706663.