William L. Dahut

The goal of prostate cancer screening is to reduce morbidity and mortality through the early detection of clinically significant disease. Accumulating evidence shows that prostate‐specific antigen (PSA)‐based screening significantly reduces prostate cancer mortality and advanced‐stage diagnosis, and approaches to reduce harms associated with screening are increasingly being used. The ACS conducted a systematic review and commissioned a modeling study to evaluate PSA‐based screening strategies, and concluded that the benefits of screening outweigh the harms. Before initiating screening, clinicians should ensure that patients are informed about the benefits, limitations, and harms of screening; the potential follow‐up evaluations of elevated PSA levels; and the expectation that low‐risk cancers will initially be managed with active surveillance. The ACS recommends biennial screening from ages 50‐69 years for average‐risk men (i.e., non‐Black men without a family history of prostate cancer). Annual screening from ages 45‐69 years is recommended for Black men. Annual screening from ages 45–69 years is recommended for non‐Black men with a strong family history (i.e., multiple first‐degree relatives diagnosed with prostate cancer at any age or one diagnosed before age 65 years). Biennial screening from ages 45‐69 years is recommended for non‐Black men with a single first‐degree relative diagnosed at age 65 years or older. For men ages 70–74 years, the balance of benefits and harms is uncertain, and individualized decision making is recommended. The ACS recommends further evaluating men ages 45–69 years with PSA levels ≥3.0 ng/mL and men ages 70–74 years with PSA levels ≥6.5 ng/mL. Most men who have elevated PSA levels confirmed on repeat testing should be offered magnetic resonance imaging and/or a validated biomarker test to guide biopsy decisions. Screening is not recommended for men with a life expectancy <10 years and should be discontinued at age 75 years.

Background: In a new era of multicancer early detection (MCED), late‐stage incidence has been proposed as an end point for the evaluation of test efficacy, marking a departure from the established end point of cancer mortality. Methods: The American Cancer Society convened a panel of 15 academic researchers with expertise in cancer screening evaluation to develop principles assuring the validity and interpretability of MCED trials with late‐stage incidence end points and advancing implementation of tests with potential for meaningful clinical utility. Results: The definition of late‐stage cancer is critical and affects study design, interpretation, and outcomes. The authors of the Peachtree Consensus recommend considering cancer‐type–specific definitions of late stage and paying attention to comparability of staging intensity in both trial arms. The duration of screening and the follow‐up interval after the last screen should be chosen based on the preclinical early stage and late‐stage durations of the target cancer types. The authors also recommend reporting aggregate results and results for individual cancer types as numbers permit and summarizing relative and absolute benefits. Predicted mortality reductions should be calculated to contextualize a late‐stage result and the inputs and assumptions involved should be reported. Given a significant late‐stage reduction suggestive of meaningful clinical benefit, the authors support launching consortium and demonstration studies while continuing to track trial mortality outcomes. Conclusions: Trials with late‐stage incidence end points that are conducted using these principles should support the development of evidence‐based screening guidelines as well as the creation of accessible data resources for observational and modeling studies.

PURPOSE: The continuous development of new imaging approaches, molecular phenotyping, genetic subtypes, prognosis assessments, and effective therapies across a range of disease states has created a need to redefine terminology and best practices for clinical trial conduct in patients with advanced prostate cancer. Methods: We convened an international expert committee of diverse working groups, the Prostate Cancer Working Group 4 (PCWG4), between 2016 and 2025. Our objective was to formulate updated criteria based on emerging evidence and clinical trial data in a biomarker context to provide guidance for clinical trial design, eligibility, and end point assessments for patients with advanced prostate cancer. RESULTS: PCWG4 redefines terminology around the disease state and previous therapies in a patient-centric context and terminology focused on androgen pathway modulation. We consider imaging, with a particular focus on positron emission tomography (PET)–defined disease. New recommendations are provided for disease state terminology, defining eligibility criteria, response and delay/prevent end points, intervals for reassessments including imaging, and patient-reported outcome determination. We provide recommendations in a biomarker-based context of use for the intended indication, reflective of patient benefit for specific interventions. We emphasize the need for development of validated PET imaging and molecular and phenotypic criteria as well as trial designs to appropriately risk stratify patients, predict and assess benefit, and measure post-treatment outcomes reliably in a trial framework. CONCLUSION: PCWG4 updates recommendations on patient and tumor characterization, therapy development, and imaging criteria and extends guidance into earlier androgen pathway modulator–naïve/sensitive disease states to reflect an evolving, heterogeneous, and diverse patient population to optimize treatment benefits for all patients.

Since 2021, the American Cancer Society has published its biennial report on the status of cancer disparities in the United States. In this 2025 report, the authors provide updated data on disparities in cancer occurrence and outcomes by sex, race, ethnicity, socioeconomic status (SES [educational attainment as a proxy]), and geographic location (including urbanicity of county of residence and congressional district), along with contributors to these disparities, including major cancer risk factors, screening, and select social determinants of health (SDOH) and health‐related social needs. The authors found substantial disparities across the cancer continuum, including risk factors, incidence, stage at diagnosis, receipt of care, survival, and mortality for many cancers and in evaluated SDOH by race and ethnicity, educational attainment, and geographic location. During 2019 through 2023, Black and American Indian/Alaska Native populations had the highest cancer mortality rates, both overall and for the leading causes of cancer death. Cancer mortality rates were also consistently higher among adults with lower SES. However, differences in cancer mortality were substantially larger by education than by race, indicating that SES plays a major role in driving racial disparities in cancer mortality. Overall cancer mortality rates were higher in Black adults than in White adults with the same education level by 7%–28% among males and by 2%–43% among females. Within each race, however, overall cancer mortality rates were higher in adults with ≤12 years of education than in those with ≥16 years of education by 143%–192% among males and by 71%–140% among females. Mortality from all cancers combined was 21% higher in nonmetropolitan than in large metropolitan counties, with the greatest differences for lung (45%) and cervical (36%) cancers and the smallest for prostate, female breast, and pancreatic cancers (7%–8%). By congressional district, the highest cancer mortality rates both overall and for lung, colorectal, and breast cancers were largely found in the South and East North‐Central division of the Midwest; however, for prostate cancer, there was no distinct geographic pattern. Sociodemographic groups that had higher cancer mortality generally had higher exposure to risk factors, lower health insurance coverage, and limited access to cancer prevention, early detection, and treatment compared with groups that had lower cancer mortality, largely reflecting fundamental disparities in SDOH. Mitigating cancer disparities in the United States requires intersectoral stakeholder engagement, targeted funding, effective policies at the federal, state, and local levels, and broad implementation of evidence‐based interventions, such as expanding health insurance coverage, including through strengthening Marketplaces and protecting and expanding access to Medicaid.

Prostate cancer is the most common cancer among men in the United States, and the incidence of advanced disease is increasing rapidly. This article provides an overview of prostate cancer occurrence using population‐based incidence and mortality data from the National Cancer Institute and the Centers for Disease Control and Prevention. Prostate cancer incidence trends have reversed from a decline of 6.4% per year during 2007 through 2014 to an increase of 3.0% annually during 2014 through 2021. The increasing trend is confined to distant‐stage disease in men younger than 55 years and to regional/distant‐stage disease in men aged 55–69 years but includes early stage disease in men aged 70 years and older. Over the past decade of data, distant‐stage disease has increased by 2.6% annually in men younger than 55 years, 6.0% annually in men aged 55–69 years, and 6.2% annually in men aged 70 years and older. American Indian/Alaska Native, Asian American/Pacific Islander, and Hispanic men are less likely than Black and White men to be diagnosed with localized disease (64%–67% vs. 71%–72%). Compared with White men, American Indian/Alaska Native men have 12% higher prostate cancer mortality despite 13% lower incidence, whereas Black men have double the prostate cancer mortality, with 67% higher incidence. In summary, continued increases in the diagnosis of advanced prostate cancer and persistent racial disparities underscore the need for redoubled efforts to optimize early detection while limiting overdiagnosis and to understand and address barriers to equitable outcomes.

Telemedicine has routinely been used in cancer care delivery for the past 3 years. The current state of digital health provides convenience and efficiency for both health-care professional and patient, but challenges exist in equitable access to virtual services. As increasingly newer technologies are added to telehealth platforms, it is essential to eliminate barriers to access through technical, procedural, and legislative improvements. Moving forward, implementation of new strategies can help eliminate disparities in virtual cancer care, facilitate delivery of treatment in the home, and improve real-time data collection for patient safety and clinical trial participation. The ultimate goal will be to extend high-quality survival for all patients with cancer through improved digital delivery of cancer care.

To resist lineage-dependent therapies such as androgen receptor inhibition, prostate luminal epithelial adenocarcinoma cells often adopt a stem-like state resulting in lineage plasticity and phenotypic heterogeneity. Castrate-resistant prostate adenocarcinoma can transition to neuroendocrine (NE) and occasionally to amphicrine, co-expressed luminal and NE, phenotypes. We developed castrate-resistant prostate cancer (CRPC) patient-derived organoid models that preserve heterogeneity of the originating tumor, including an amphicrine model displaying a range of luminal and NE phenotypes. To gain biological insight and to identify potential treatment targets within heterogeneous tumor cell populations, we assessed the lineage hierarchy and molecular characteristics of various CRPC tumor subpopulations. Transcriptionally similar stem/progenitor (St/Pr) cells were identified for all lineage populations. Lineage tracing in amphicrine CRPC showed that heterogeneity originated from distinct subclones of infrequent St/Pr cells that produced mainly quiescent differentiated amphicrine progeny. By contrast, adenocarcinoma CRPC progeny originated from St/Pr cells and self-renewing differentiated luminal cells. Neuroendocrine prostate cancer (NEPC) was composed almost exclusively of self-renewing St/Pr cells. Amphicrine subpopulations were enriched for secretory luminal, mesenchymal, and enzalutamide treatment persistent signatures that characterize clinical progression. Finally, the amphicrine St/Pr subpopulation was specifically depleted with an AURKA inhibitor, which blocked tumor growth. These data illuminate distinct stem cell (SC) characteristics for subtype-specific CRPC in addition to demonstrating a context for targeting differentiation-competent prostate SCs.

Patients diagnosed with localized high-risk prostate cancer have higher rates of recurrence, and the introduction of neoadjuvant intensive hormonal therapies seeks to treat occult micrometastatic disease by their addition to definitive treatment. Sufficient profiling of baseline disease has remained a challenge in enabling the in-depth assessment of phenotypes associated with exceptional vs. poor pathologic responses after treatment. In this study, we report comprehensive and integrative gene expression profiling of 37 locally advanced prostate tumors prior to six months of androgen deprivation therapy (ADT) plus the androgen receptor (AR) inhibitor enzalutamide prior to radical prostatectomy. A robust transcriptional program associated with HER2 activity was positively associated with poor outcome and opposed AR activity, even after adjusting for common genomic alterations in prostate cancer including PTEN loss and expression of the TMPRSS2:ERG fusion. Patients experiencing exceptional pathologic responses demonstrated lower levels of HER2 and phospho-HER2 by immunohistochemistry of biopsy tissues. The inverse correlation of AR and HER2 activity was found to be a universal feature of all aggressive prostate tumors, validated by transcriptional profiling an external cohort of 121 patients and immunostaining of tumors from 84 additional patients. Importantly, the AR activity-low, HER2 activity-high cells that resist ADT are a pre-existing subset of cells that can be targeted by HER2 inhibition alone or in combination with enzalutamide. In summary, we show that prostate tumors adopt an AR activity-low prior to antiandrogen exposure that can be exploited by treatment with HER2 inhibitors. ClinicalTrials.gov registration: NCT02430480 .