Simple SummaryThis review article details new precision oncology-based therapeutics used to treat advanced prostate cancer. Metastatic castration-resistant prostate cancer remains an incurable diagnosis, however newly identified biomarkers have expanded treatment repertories for some patients with progressive disease. Advancements in immune checkpoint inhibitors, therapeutics that exploit DNA damage response deficiencies, and new innovations in radioligand therapies and theranostics are detailed. This article highlights the potential and real-world application of precision oncology to improve outcomes for patients with prostate cancer by tailoring treatment to the individual characteristics of each patient’s tumor.AbstractProstate cancer (PC) is the second leading cause of cancer death in men in the United States. While diversified and improved treatment options for aggressive PC have improved patient outcomes, metastatic castration-resistant prostate cancer (mCRPC) remains incurable and an area of investigative therapeutic interest. This review will cover the seminal clinical data supporting the indication of new precision oncology-based therapeutics and explore their limitations, present utility, and potential in the treatment of PC. Systemic therapies for high-risk and advanced PC have experienced significant development over the past ten years. Biomarker-driven therapies have brought the field closer to the goal of being able to implement precision oncology therapy for every patient. The tumor agnostic approval of pembrolizumab (a PD-1 inhibitor) marked an important advancement in this direction. There are also several PARP inhibitors indicated for patients with DNA damage repair deficiencies. Additionally, theranostic agents for both imaging and treatment have further revolutionized the treatment landscape for PC and represent another advancement in precision medicine. Radiolabeled prostate-specific membrane antigen (PSMA) PET/CT is rapidly becoming a standard of care for diagnosis, and PSMA-targeted radioligand therapies have gained recent FDA approval for metastatic prostate cancer. These advances in precision-based oncology are detailed in this review.