This narrative review summarizes current evidence regarding the epidemiology, diagnosis, and management of localized and metastatic prostate cancer.
— Read on jamanetwork.com/journals/jama/fullarticle/2831269

Prostate Cancer A Review

Abstract

Importance  Prostate cancer is the most common nonskin cancer in men in the US, with an estimated 299 010 new cases and 35 250 deaths in 2024. Prostate cancer is the second most common cancer in men worldwide, with 1 466 680 new cases and 396 792 deaths in 2022.

Observations  The most common type of prostate cancer is adenocarcinoma (≥99%), and the median age at diagnosis is 67 years. More than 50% of prostate cancer risk is attributable to genetic factors; older age and Black race (annual incidence rate, 173.0 cases per 100 000 Black men vs 97.1 cases per 100 000 White men) are also strong risk factors. Recent guidelines encourage shared decision-making for prostate-specific antigen (PSA) screening. At diagnosis, approximately 75% of patients have cancer localized to the prostate, which is associated with a 5-year survival rate of nearly 100%. Based on risk stratification that incorporates life expectancy, tumor grade (Gleason score), tumor size, and PSA level, one-third of patients with localized prostate cancer are appropriate for active surveillance with serial PSA measurements, prostate biopsies, or magnetic resonance imaging, and initiation of treatment if the Gleason score or tumor stage increases. For patients with higher-risk disease, radiation therapy or radical prostatectomy are reasonable options; treatment decision-making should include consideration of adverse events and comorbidities. Despite definitive therapy, 2% to 56% of men with localized disease develop distant metastases, depending on tumor risk factors. At presentation, approximately 14% of patients have metastases to regional lymph nodes. An additional 10% of men have distant metastases that are associated with a 5-year survival rate of 37%. Treatment of metastatic prostate cancer primarily relies on androgen deprivation therapy, most commonly through medical castration with gonadotropin-releasing hormone agonists. For patients with newly diagnosed metastatic prostate cancer, the addition of androgen receptor pathway inhibitors (eg, darolutamide, abiraterone) improves survival. Use of abiraterone improved the median overall survival from 36.5 months to 53.3 months (hazard ratio, 0.66 [95% CI, 0.56-0.78]) compared with medical castration alone. Chemotherapy (docetaxel) may be considered, especially for patients with more extensive disease.

Conclusions and Relevance  Approximately 1.5 million new cases of prostate cancer are diagnosed annually worldwide. Approximately 75% of patients present with cancer localized to the prostate, which is associated with a 5-year survival rate of nearly 100%. Management includes active surveillance, prostatectomy, or radiation therapy, depending on risk of progression. Approximately 10% of patients present with metastatic prostate cancer, which has a 5-year survival rate of 37%. First-line therapies for metastatic prostate cancer include androgen deprivation and novel androgen receptor pathway inhibitors, and chemotherapy for appropriate patients.

Introduction

An estimated 299 010 new diagnoses of prostate cancer were made in the US in 2024.1 Prostate cancer is heterogeneous and presentation ranges from an asymptomatic, screen-detected lesion that may never progress to an aggressive malignancy, representing a leading cause of morbidity and mortality worldwide.2,3 Therefore, individualized strategies for screening and management of localized prostate cancer are needed to avoid overtreatment while also preventing progression to metastatic disease.

The most common type of prostate cancer is adenocarcinoma (≥99%).4 Primary neuroendocrine prostate cancer, including small-cell prostate cancer, is rare5 and will not be discussed further in this Review. Prostate adenocarcinomas are stimulated by androgen receptor signaling. Therefore, androgen deprivation therapy (ADT) is the primary treatment for patients with prostate cancer for whom systemic treatment is indicated.6 ,7 Recent insights into the biology of prostate cancer have led to new diagnostic tools, such as prostate cancer–specific positron emission tomography (PET), and new therapeutic strategies, including more effective androgen receptor inhibition, cytotoxic chemotherapy, and cell surface antigen–targeted therapies. This Review summarizes current evidence regarding the epidemiology, diagnosis, and management of localized and metastatic prostate cancer. A summary of the risk factors and treatments for prostate cancer appears in the Box.

Risk Factors and Treatments for Localized and Metastatic Prostate Cancer

What are the main risk factors for prostate cancer?

• Older age, genetic factors, and Black race are the strongest risk factors associated with the development of prostate cancer.

• Germline alterations in genes involved in DNA damage repair are found in 12% of patients with metastatic prostate cancer.

What is the most effective therapy for localized prostate cancer?

• Treatment of localized prostate cancer depends on risk stratification (defined by serum prostate-specific antigen level, clinical tumor staging based on digital rectal examination, and Gleason score or group), life expectancy, and personal preference.

• For many patients with low-risk or favorable intermediate-risk disease, active surveillance with serial prostate-specific antigen screenings, digital rectal examinations, prostate biopsies, and magnetic resonance imaging may be considered.

• Patients with higher-risk disease may be treated either with radical prostatectomy or radiation therapy.

What is first-line treatment for newly diagnosed metastatic prostate cancer?

• For most patients with newly diagnosed metastatic prostate cancer, androgen deprivation therapy with orchiectomy or a gonadotropin agonist or antagonist should be used.

• Treatment should also include androgen deprivation in combination with an androgen receptor pathway inhibitor (such as abiraterone or enzalutamide).

• The addition of chemotherapy (docetaxel) may be considered for some patients, especially those with more advanced disease.

Methods

A PubMed search was conducted to identify English-language articles describing observational studies, randomized clinical trials, meta-analyses, and systematic reviews of prostate cancer published between January 1, 2014, and December 11, 2024. A total of 401 randomized clinical trials, 203 meta-analyses, and 291 systematic reviews were identified. Randomized clinical trials were prioritized for inclusion. This Review includes a total of 114 articles (39 randomized clinical trials, 43 observational cohort studies, 9 meta-analyses, 9 systematic reviews, and 14 guideline recommendations), including publications prior to 2014.

Observations and Discussion

Epidemiology and Risk Factors

There were an estimated 3 399 229 men living with prostate cancer in the US in 2021.1 Prostate cancer is the second most common cause of cancer and cancer death among men in the US, with an estimated 35 250 deaths in 2024.1 Prostate cancer is also the second most common cause of cancer in men worldwide, with 1 466 680 new cases and 396 792 deaths in 2022.2 Incidence varies, with the highest age-standardized rates observed in Northern Europe (82.8 per 100 000 person-years), Australia (78.1 per 100 000 person-years), the Caribbean (73.8 per 100 000 person-years), and North America (73.5 per 100 000 person-years), likely due to a combination of increased prostate-specific antigen (PSA) screening, life expectancy, genetics, and modifiable risk factors such as diet and obesity.2,8

Prostate cancer occurs predominantly in older men and the median age at diagnosis is 67 years (IQR not available).1 Data from autopsy series show a nonlinear increase in cases of occult prostate cancer with advancing age; 59% of men older than 79 years had histological evidence of prostate cancer.9,10 The annual incidence rate of prostate cancer is 173.0 cases per 100 000 Black men vs 97.1 per 100 000 White men and the mortality rate is 38.7 per 100 000 Black men per year vs 18.0 per 100 000 White men per year.1 The reasons for the disparities in incidence and mortality are complex and not entirely understood. After accounting for differences in incidence, disparities in mortality persist and may reflect inequities in access to health care, the quality of care received, and presence of more aggressive cancer biology.11-13

Prostate cancer is highly hereditable. Results from twin studies performed in Northern Europe reported that more than 50% of prostate cancer risk is attributable to genetic factors.14 A registry study conducted in Sweden, including 51 897 brothers of 32 807 men with prostate cancer, reported that men with a brother who had prostate cancer had a 14.9% (95% CI, 14.1%-15.8%) probability of having prostate cancer at 65 years of age and a 30.3% (95% CI, 29.3%-31.3%) probability at 75 years of age.15

A genome-wide association study16 identified 451 genomic variants associated with risk for prostate cancer. A risk score based on these genomic variants stratified individuals effectively: 51.2% of prostate cancer cases occurred in the top quintile of risk vs 4.4% of cases in the bottom quintile. A germline analysis of 692 men with metastatic prostate cancer unselected for family cancer history identified 11.8% with a pathogenic alteration in a DNA repair gene, most commonly BRCA2 (5.3%).17 Guidelines from the National Comprehensive Cancer Network (NCCN) and the European Society of Medical Oncology recommend panel-based germline genetic testing for all patients with high-risk localized or metastatic prostate cancer, regardless of family history, to inform cascade genetic testing of relatives and the use of precision therapies targeting these gene alterations.18-20