Advancing the Evidence Base to Guide Treatment Decisions for Low-Risk Prostate Cancer in the United States - ABSTRACT Active surveillance (AS) is increasingly recommended for men diagnosed with low-risk prostate cancer (PCa), yet many patients ultimately transition to active treatment (AT), including radical prostatectomy or radiation therapy, after diagnosis. However, real-world evidence on the long-term comparative clinical and patient- reported outcomes (PROs) of early and delayed AT versus AS remains limited among patients with low-risk PCa in the United States. Delayed AT represents a common but understudied management pathway in which patients initially monitored with AS escalate to AT one to three years post-diagnosis. This proposal will evaluate the long-term effectiveness, adverse events, and PROs associated with early and delayed radical prostatectomy, radiation therapy, and AS among men with low-risk PCa in Kaiser Permanente Northern California (KPNC), a large integrated healthcare system with rich longitudinal clinical and administrative data. We will conduct two parallel cohort studies: (1) a real-world study of clinical outcomes in approximately 15,700 men diagnosed at KPNC from 2010 to 2027 with early-stage PCa (defined as prostate-specific antigen ≤10 ng/mL, Gleason score ≤6, and clinical stage ≤T2a); and (2) an evaluation of PROs within the Patient REported outcomes for Prostate cARE (PREPARE) Study, a sub-cohort of 1,139 men diagnosed with low-risk PCa from 2012 to 2014. We will assess clinical outcomes through 2029, including progression-free survival, all-cause and PCa-specific mortality, metastasis, and treatment-related complications such as cardiovascular events, fractures, and urinary tract infections. Among PREPARE participants, we will evaluate long-term quality of life PROs—including functional, psychosocial, and decisional outcomes. This cohort was originally surveyed at baseline, 6 months, and 24 months post-diagnosis; we will now conduct a new follow-up approximately 15 years post-diagnosis. Primary analyses will compare outcomes across radical prostatectomy, radiation therapy, and AS. We will also assess and contrast outcomes of both early and delayed administration of prostatectomy and radiation therapy to determine how treatment timing and modality influence long-term outcomes. This study will generate critical real-world evidence on the benefits, harms, and quality-of-life impacts of different management pathways, addressing a key gap in the comparative long-term outcomes of low-risk PCa. Findings will inform more personalized treatment decisions for patients and healthcare providers and have the potential to guide future updates to clinical practice guidelines in the United States.
