Prostate adenocarcinoma is driven by the lineage-specific transcription factor androgen receptor (AR), with androgen deprivation and AR pathway inhibitors (ARPIs) being highly effective treatments that are a mainstay in the clinic. However, therapeutic resistance that bypasses ARPIs eventually develops due to emergence of tumor heterogeneity highlighted by the acquisition of AR alterations and diverse phenotypic states, including cells with heightened plasticity and divergent lineage features. The availability of genomic datasets across the prostate cancer treatment continuum enables unprecedented insight into the molecular alterations underpinning disease progression and treatment resistance. We explored the transcriptomes of >1,000 patients with primary prostate cancer, metastatic castration-resistant prostate cancer (mCRPC) and neuroendocrine prostate cancer (NEPC). Analysis of these data and projection along a pseudotime axis revealed gene expression patterns driving prostate cancer progression. Pseudotime analysis showcased that AR signaling and luminal marker expression increase during primary tumor formation and remain elevated in the early stages of mCRPC. The eventual reduction in AR expression, AR signaling and luminal identity during mCRPC may facilitate lineage plasticity and cell state reprogramming. Integrated analysis of prostate tumors across treatment lines additionally identified cell cycle-associated genes and epigenetic regulators whose expression increase from primary to mCRPC and NEPC tumors, suggesting that they play a key role in driving molecular heterogeneity necessary to circumvent ARPI treatments. One such epigenetic regulator identified, the polycomb repressive complex 2 (PRC2), is a compelling and tractable target for prostate cancer. Rinzimetostat (ORIC-944) is a next-generation, potent, highly selective, orally bioavailable small molecule inhibitor of PRC2 that allosterically targets the EED subunit, with potential best-in-class drug properties including reduced drug-drug interaction liabilities and superior half-life as compared to other clinical compounds. Rinzimetostat in combination with the ARPI darolutamide demonstrated antitumor activity across a breadth of in vivo models representing the prostate cancer continuum and capturing a broad spectrum of treatment resistance settings including castration-sensitive and -resistant, ARPI-sensitive and -resistant, and AR-mutant and -wildtype. Thus, rinzimetostat represents a promising therapy to re-sensitize resistant tumors to ARPIs and block prostate tumor adaptation. Rinzimetostat is under clinical evaluation in combination with AR inhibitors in a global Phase 1b study (NCT05413421).