This document was last amended in November 2024 to reflect literature that was released since the original publication of this content in May 2013. This document will continue to be periodically updated to reflect the growing body of literature related to this topic.

Keywords: Prostate Cancer, PSA, Screening, Radical Prostatectomy

Learning Objectives

At the end of medical school, the medical student will be able to:

1. Identify the basics of prostate anatomy and physiology
2. Describe the epidemiological features of prostate cancer
3. Describe the controversy surrounding prostate cancer screening
4. Describe the general approaches to prostate cancer screening and diagnosis
5. List the major components of prostate cancer staging
6. Describe the basic treatment options for localized and advanced prostate cancer

Introduction

The following lesson is meant to summary basic knowledge appropriate for a medical student on the topic of prostate cancer. This will include basic prostate anatomy and physiology as well and guideline-based management approaches for prostate cancer screening and treatment.

Summary

Basic Prostate Anatomy and Function

The prostate is a male sex accessory gland located within the pelvis below the bladder and above the urogenital diaphragm. The prostate encircles the urethra like a doughnut and is embryologically derived from the urogenital sinus (Figure 1). The prostate has four primary anatomic zones: the anterior zone, the peripheral zone, the central zone, and the transition zone. The majority of prostate cancers arise in the peripheral zone of the prostate, whereas benign prostatic hyperplasia (BPH) occurs in the transition zone. Since most of the peripheral zone is located posteriorly and the prostate is directly anterior to the rectum, prostate tumors that form nodules can often be palpated on a digital rectal exam (DRE; Figure 2). Additionally, since the peripheral zone is relatively distant from the urethra, men with prostate cancer most often have no urinary symptoms. With regards to BPH, the prostate continues to grow (hyperplasia) predominantly in the transition zone with age. These benign changes can cause voiding symptoms mainly due to obstruction.

Figure 1. Prostate Anatomy

Figure 2. Digital rectal exam of the prostate

The role of the prostate is to secrete about 30% of the fluid that comprises the ejaculate. Prostatic secretions help prolong the lifespan of sperm in the vagina and contains high amount of zinc and a substance called prostate-specific antigen (PSA). PSA is an enzyme responsible for the liquefaction of semen and is normally only present in small amounts in serum.

Epidemiologically, prostate cancer is the most common solid organ cancer in men and is currently the second leading cause of cancer death in men after lung cancer in the United States. About 1 in 9 men in the United States will be diagnosed with prostate cancer, and over 3 million men have a prior diagnosis of prostate cancer. The highest risks are observed in Black men, older men (average age at diagnosis around 66), and those with a first-degree relative (brother or father) with prostate cancer.

Prostate Cancer Screening: Background of Controversies

The clinical use of serum PSA to detect prostate cancer emerged in the late 1980s and revolutionized prostate cancer detection, leading to a surge in early-stage diagnosis in the 1990s. Prior PSA screening, men with prostate cancer would most often present symptomatically with incurable, metastatic disease.

Subsequent studies revealed that a significant portion of prostate cancers did not require immediate treatment. Many men were being overtreated, undergoing surgery or radiation for cancers that would not have caused health issues during their lifetime. These treatments often resulted in adverse effects, such as bowel, urinary, and sexual dysfunction.

In response to these findings, the United States Preventive Services Task Force (USPSTF), an influential panel of experts that provides evidence-based recommendations on preventive and screening measures for American patients, revised its guidance on prostate cancer screening. In 2008, the USPSTF recommended against routine prostate cancer screening for men older than 75, recognizing that these men often die from causes unrelated to prostate cancer. By 2012, the USPSTF broadened its recommendation, advising against routine screening for all men, suggesting that the harms of screening outweighed the benefits. (Figure 3.)

Importantly, these recommendations were largely based on the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial conducted in the United States, which found no difference in mortality between men randomized to screened or unscreened groups. However, several issues emerged following the 2012 guidance. Notably, the amount of contamination (PSA screening) in the control arm of the PLCO trial was found to be substantial, which likely minimized the measured effect of screening in the treatment arm. Additionally, in trials from Europe where contamination was lower, there was a reduction in mortality among men screened for prostate cancer. Screening was also found to result in decreased incidence of metastatic prostate cancer, a condition which can lead to significant morbidity due to the cancer itself and the additional treatments needed. Finally, the indolent course of some low-grade prostate cancers had been noted, leading to a shift in clinical practice, with more urologists managing these men with surveillance strategies to minimize overtreatment (see “Localized prostate cancer management” below).

As a result, the USPSTF updated its guidelines on prostate cancer screening in 2018. For men aged 55 to 69, they recommended that the decision to initiate screening should be made after an informed conversation between the patient and their clinicians about the risk and benefits of screening. For men aged 70 and older, the recommendation against screening was maintained. 

Figure 3. Timeline of Screening Guidelines

Prostate Cancer Screening: Who?

Primary care physicians are often the first to conduct prostate cancer screening, while urologists typically focus on evaluating patients with positive screening results to determine if a biopsy if necessary. The AUA provides the following guidance on this process:

• men age 40 to 45 years: consider initiating screening for men at a higher risk of prostate cancer including those of Black race, those with certain genetic mutations, and those with a family history of prostate cancer (especially first-degree relatives or multiple generation of affected relatives diagnosed at younger ages). I
• men 50 to 69 years: most likely to benefit from routine screening. For that reason, these men should start screening after an informed decision-making process regarding the risk and benefits of screening (See “Prostate cancer screening: The risk and benefits” below).
• men age 70+”: Screening is generally not recommended, particularly for men with a life expectancy of less than 10 years as they most likely have other healthcare issues that should be prioritized over treatment of asymptomatic prostate cancer. However, healthy men older than 70 may still benefit from screening.

Prostate Cancer Screening: The Risk and Benefits

Discussing the risks and benefits of prostate cancer screening is critical to a complete decision-making process for those considering initiating screening. Decision aid tools supplied by reputable clinical societies (e.g. the American Cancer Society and AUA) should be recommended to patients when discussing screening.   

The benefits of screening include finding and treating prostate cancer before it has metastasized outside of the prostate. This would prevent not only the comorbidities and shortened expected life-span due to metastatic prostate cancer but would also obviate the need for life-long androgen deprivation therapy and other systemic therapies used to treat metastatic prostate cancer. The risks of prostate cancer screening are many and should be discussed with all patients considering screening. Bleeding and infectious complications following a prostate biopsy can lead to hospitalizations. Men who undergo surgery or radiotherapy can expect issues with erectile, bowel, and urinary dysfunction depending on the actual treatment. For those who undergo active surveillance, many will still eventually receive surgery or radiotherapy and some who stay on surveillance experience anxiety related to harboring an untreated cancer.

Although many sources exist to estimate an individual patient’s risk of aggressive prostate cancer and adverse effects related to treatment, ultimately a complete discussion of the risk benefits includes assessing the patient’s priorities when it comes to prostate cancer screening.

Prostate Cancer Screening: How?

The AUA recommends men who have agreed to initiate screening following a shared decision-making process be screened at an interval of every two to four years. This interval is expected to reduce the risk of overdiagnosis compared to annual screening without compromising the benefits of screening. The screening interval should be personalized based on the patient’s preferences, age, PSA, and other medical issues.

The interpretation of a serum PSA value should be made in the context of the entire patient. Several factors outside of prostate cancer can lead to elevated PSA including inflammation/infection, prostate enlargement (BPH), and recent genitourinary tract manipulation (e.g. urethral catheter or cystoscopy). Generally, PSA-based screening should only be performed well after (greater than 4 weeks) a potential infection or prostate manipulation has occurred. No strict PSA cutoff for referral or biopsy exists. Age-specific PSA guidelines exist and can help primary care providers make appropriate referrals to urologists (Table 1).

Table 1. General screening PSA cutoffs for referral to urologist

Patient age (years)	PSA (ng/mL)
<50	≥1.5
50–54	≥2.0
55–59	≥3.0
60–69	≥4.0
≤70	≥6.0

Several tools help incorporate multiple factors to help predict the risk a patient may harbor a high-grade cancer. For instance, the Prostate Biopsy Collaborative Group Calculator uses prospective data to generate an individual patient’s risk along with visual graphics to use in a patient encounter (https://riskcalc.org/PBCG/)

Once a referral to a urologist is made, the urologist may use an array of adjunct tests to form a recommendation and need for a prostate biopsy (Table 2). Aside from the DRE which is used almost universally in conjunction with PSA measurements for screening, the rest of the tests are used variably based on the urologist’s experience and test availability.

Table 2: Adjunct prostate cancer screening tests

Adjunct pre–biopsy tests	Notes
PSA kinetics	Rapid and sustained PSA rises are more indicative of cancer
Free/total PSA ratio	Lower ratio of unbound (free) to total serum PSA suggests a higher risk of cancer
Serum Markers (e.g. PHI, 4Kscore, ISOPSA) PP	Determines risk of prostate cancer based on the different molecular forms of serum PSA
Magnetic resonance imaging	Scores lesions in the prostate based on risk of harboring aggressive prostate cancer. Can also be used to aid targeted biopsies and focal therapy
Digital rectal exam (DRE)	Palpation of a nodule or induration can be indicative of a prostate cancer
Urinary markers (e.g. PCA3, ExoDx, SelectMDx)	Can help predict the risk of prostate cancer

As a final point, prostate cancer screening should cease if a given patient’s health status changes and other health issues take priority over detecting asymptomatic prostate cancer.

Diagnosing Prostate Cancer

The diagnosis of prostate is made with histological evidence from a biopsy of the prostate except in some case of metastatic disease. This can be done transrectally or transperineally with the use of an ultrasound probe that is  placed in the rectum of the patient (Figure 4). Usually at least 12 cores are sampled in a systematic manner that assesses the peripheral zone.

Figure 4. Prostate biopsy via transrectal ultrasound

The most common complications of prostate biopsies include those related to bleeding, infection, and urinary retention. Bleeding may occur in the urine and ejaculate and patients should be counseled to expect these for several weeks after the biopsy. All patients should also be advised that any unexplained fever in the 4 weeks following a biopsy, and especially those with urinary symptoms warrants an emergency department visit for potential acute prostatitis. The risk of a hospitalization following a prostate biopsy is less than 3% in the United States.

Recent advancements in magnetic resonance imaging (MRI) have led to the incorporation of the MRI into prostate cancer detection. MRI may be used to help locate tumors in men with a high suspicion of prostate cancer but a prior negative biopsy. They may also help urologists target tumors in the prostate to help increase the yield of high-grade tumor detection and lower the detection of low grade, indolent tumors.

Finally, in the United States, interest in transperineal prostate biopsies has increased. Although a transrectal ultrasound is still used to target the prostate, the avoidance of a transrectal biopsy has the potential to substantially reduce the infection risk and need for broad antibiotics. Recent data has also shown transperineal biopsies might not require any systemic antibiotics which has substantial implications for antibiotic stewardship. This modality is still being compared to the transrectal approach and optimized in terms of the anesthetic block employed to make the office-based procedure tolerable to patients.

Prostate Cancer Staging, Grading, and Risk Groups

The four relevant tools to risk stratifying patients include American Joint Committee on Cancer (AJCC) TNM staging (Figure 5), grade group, and National Comprehensive Cancer Network (NCCN) risk groups for localized disease, and disease burden for metastatic disease. For urologist, familiarity with these tools helps guide further cancer evaluations and management options. TNM staging is based on the most recent edition of AJCC. The most relevant distinctions to make at the time of diagnosis include non-palpable on DRE (cT1) vs palpable (cT2) and the presence of pathologically enlarges lymph nodes or metastatic disease based on imaging which most often includes a CT and bone scan.

Figure 5. TNM Staging

Prostate cancer is typically an adenocarcinoma, assessed by the degree of architectural abnormality on the biopsy which is based on the Gleason Grade (scale of 1-5). A grade of 1 indicates well-differentiated tissue similar to normal prostate glands, while 5 represents poorly differentiated tissue. The Gleason Score combines the most predominant and second most predominant patterns, commonly written as “primary+ secondary.” These are further divided into Gleason Groups 1 to 5 based on the 2016 guidelines from the International Society of Urological Pathology (ISUP; Table 3).

Table 3: Gleason grade groups

Gleason score	Grade group
3+3=6	1
3+4=7	2
4+3=7	3
8	4
9-10	5

For men with localized prostate cancer, the NCCN groups ultimately refine precision care through ongoing updates to guidelines. Key components of the risk groups include grade group, PSA at time of diagnosis, TNM staging, and the amount of biopsy cores with cancer. Patients in lower risk groups are not recommended to receive additional imaging due to low risk of metastasis. In contrast, men with higher risk disease, those with family history, or specific histologic findings may benefit from germline DNA testing. Imaging for staging patients with high-risk prostate cancer can include bone scan with pelvic MRI or CT scans. Positron emission tomography (PET) imaging is often performed for initial staging of men with high-risk disease. While the AUA only recommends PET imaging for men with negative conventional imaging who are at a high risk for metastatic disease, the NCCN suggests that negative prior imaging is not absolutely necessary for PET use in initial staging. See below for details on PET radiotracers used for prostate cancer.

For men with metastatic prostate cancer at diagnosis, patients are often classified as having a low volume (oligometastatic) or high volume (widespread metastatic) disease. Although many definitions exist, the most common is derived from the CHAARTED randomized controlled trial which defined high volume as four or more bone metastases with one or more outside the spine or pelvis and/or any visceral metastases. These groupings may help guide the best choice for treatment but are more often applied for prognostic value.

Positron Emission Tomography (PET)

There are currently six PET tracers approved by the FDA to evaluate prostate cancer that has recurred after treatment. These are Ga-68 PSMA-11 (PSMA-HBED-CC), F-18 piflufolastat (DCFPyL), flotufolastat F-18, C-11 choline, F-18 fluciclovine, and F-18 sodium fluoride. Of these, only the tracers based on the cell membrane expression of the protein prostate-specific membrane antigen (PSMA) are approved for the initial staging of prostate cancer (Ga-68 PSMA-11, F-18 piflufolastat, and flotufolastat F-18)). In general, recent studies suggest PSMA-PET is the superior modality for prostate cancer.

Localized prostate cancer management

Given the high prevalence of prostate cancer, a basic understanding of management options are imperative for both specialist and primary care physicians.

Active surveillance and watchful waiting

In recent years, the use of surveillance approaches for men with low-risk prostate cancer has significantly increased, reaching approximately 40% in the United States. Active surveillance is defined as deferred treatment with disease monitoring with intention to treat for disease progression or patient preference. This is the preferred management option for men with low- and very low-risk prostate cancer, helping to prevent unnecessary treatment-related adverse effects. Monitoring varies by practice but typically includes DRE’s and PSA measurements every 6 to 12 months, along with regular repeat biopsies. While MRI has been tested as a form of disease monitoring tool, it should not entirely replace periodic biopsies. MRI can be used to to risk stratify patients on active surveillance. Importantly, around 50% of men who start on active surveillance will avoid definitive treatment after 10 to15 years. Watchful waiting is defined as deferred treatment except for symptomatic disease progression. Men who elect watchful waiting typically have other comorbidities that make them less suitable candidates for definitive treatments.

Radical prostatectomy

Radical prostatectomy (RP) is a management option for men with localized prostate cancer. A standard radical prostatectomy can be performed with a lower midline abdominal incision or via a minimally invasive laparoscopic approach typically with robotic assistance (Robotic assisted laparoscopic radical prostatectomy “RALP”). Men are often hospitalized for one to two nights. In this surgery, the prostate, seminal vesicles, and pelvic lymph nodes are removed. The reconstructive portion involves reconnecting the bladder neck the urethra. Men have varying degree of stress incontinence following surgery. This reliably improves in the months following surgery with Kegel exercising to strengthen the pelvic floor musculature as those muscles assume a larger role in urinary continence.

Because the cavernous nerves which help with erections run in paired bundles along the sides of the prostate, a prostatectomy can negatively affect erectile function (Figure 6). Depending on the aggressiveness of the cancer and location of the tumor in the prostate, the surgeon may be able to “spare” transecting those nerves which helps with erectile function recovery. However, in men who cannot have either pair of nerve bundles spared, erectile function will be compromised. 

Figure 6. Male reproductive system

Prostate cancer spreads to the lymph nodes first after leaving the prostate. Thus, removing the pelvic lymph nodes at the time of surgery can help with staging the disease. Men with adverse pathological features at surgery (seminal vesicle involvement, extraprostatic extension, or positive surgical margins) may benefit from radiotherapy. This can be given as adjuvant radiotherapy (RT) after primary treatment (e.g., surgery) to reduce the risk of cancer recurrence, or as salvage radiotherapy (XRT) if the cancer recurs, to control its spread. Both options aim to improve long-term cancer control.

Radiotherapy

Radiotherapy can be delivered as external beam radiotherapy (EBRT) or radioactive seed implants (brachytherapy). EBRT traditionally involves daily sessions of low-dose fractions (1.8 to 2 Gy) over the course of about 37 to 45 sessions, depending on the patient’s risk group (Figure 7). In recent years, hypofractionation EBRT—using  fewer fractions at higher dosing of radiation (2.5 to 3 Gy)-- has become more popular due to data suggesting similar outcomes. Brachytherapy consists of implanting radioactive seeds within the prostate transperineally under general anesthesia (Figure 8). Brachytherapy or EBRT monotherapy are usually for men with favorable risk localized prostate cancer. For men with higher risk disease, EBRT is combined with androgen deprivation (ADT) and sometimes with brachytherapy. The duration of ADT is individualized, ranging from 6 months to 2 years, based on cancer aggressiveness, with recent guidelines emphasizing the potential benefits of combining EBRT, brachytherapy, and ADT for optimal oncologic outcomes in men with very high-risk prostate cancer. Side effects of radiation therapy include radiation related cystitis, proctitis, irritative voiding symptoms, as well as erectile dysfunction.

Figure 7. Patient Receiving External Radiation

Figure 8. Brachytherapy

Comparing surgery and radiotherapy

In terms of oncologic outcomes, surgery and radiotherapy are considered comparable. Younger healthier men are often recommended to undergo surgery as the most significant adverse effects of radiotherapy (radiation cystitis, chronic hematuria, etc.) tend to manifest 10 to 15 years following treatment. Additionally, following surgery, radiotherapy in the form of EBRT may be offered as adjuvant or salvage treatment. While surgery can be performed following primary radiotherapy, it is not often done due to the complexity of the surgery following radiation and the substantially increased risk of incontinence and erectile dysfunction. Also, patients undergoing salvage prostatectomy are at increased risk of intraoperative rectal injury which could require colostomy.

Radiotherapy has traditionally been preferred for older patients or those with limited life expectancy, as well as individuals who are not optimal surgical candidates. However multiple studies have shown no difference in cancer outcomes when comparing surgery and radiation therapy. Patients may opt for radiotherapy to avoid the more significant short-term side effects associated with radical prostatectomy. Monitoring for cancer recurrence (post-treatment surveillance) is similar following both surgery and radiotherapy, involving routine PSA measurements for the rest of the patient’s life.

Focal therapies and other options

Other treatments exist with the purpose of providing some oncologic efficacy while minimizing treatment side effects. High-intensity focused ultrasound (HIFU) and cryotherapy represent the most common sort of these treatments, which can be used to treat the whole prostate (whole gland) or only the tumor within the prostate (focal therapy). However, most guidelines note that these treatments are currently still considered investigational as the primary treatment for prostate cancer and should only be offered in the context of a clinical trial.  Focal therapies are not recommended for patients with high-risk prostate cancer. To date, the only randomized clinical trial on prostate ablation includes patient with low-risk prostate cancer.

Advanced prostate cancer management

The AUA’s recent guidelines on advanced prostate cancer management emphasize a patient-centered approach, tailoring treatment based on life expectancy, comorbidities, tumor characteristic, and patient preferences to support shared, multidisciplinary decision-making. For patients with metastatic PCa, the guidelines recommend offering germline testing along with further somatic testing and genetic counseling  to guide therapy. The 2024 AUA guidelines on salvage therapy for patients with biochemical recurrence (BCR) post-RP highlight early intervention, advanced imaging, risk-based treatment, and personalized care (see link below). For these patients, XRT is recommended at lower PSA levels (<0.5 ng/mL), with even lower levels (<0.2 ng/mL) suggested for those with high-risk features (Table 4). Notably, recent studies have shown that early XRT is associated with improved outcomes, whereas routine adjuvant RT offers no significant benefit over PSA surveillance with early XRT, making routine adjuvant RT unnecessary.

In managing BCR, urologist can use ultrasensitive PSA testing but should delay XRT until a rising PSA trend is confirmed. For patients with BCR after initial local therapy, advanced imaging is valuable for diagnostic accuracy and to help tailor salvage therapy. PSMA-PET is the preferred imaging tool to assess the extent of recurrence and can be used as either a first-line option or if other imaging is inconclusive. Next-generation PET scans are recommended for those considering XRT, though treatment should not be delayed if scans are negative due to limited detection at low PSA levels. For suspected local recurrence, a combination of pelvic MRI with PET/CT can improve accuracy of diagnosis. For patients with positive lymph nodes (pN1) combining ADT and XRT is also advised.

Table 4: High-Risk Features to consider for counseling and management in the setting of BCR

High-risk prognostic variables

Grade Group 4-5

Stage pT3b-4

Pathological features Surgical margin status Positive nodes Extraprostatic extension

Short PSADT (< 12 months)

Short interval from primary therapy to BCR

High genomic classifier score

*This is not an exhaustive list

Biochemical recurrence without evidence of metastatic disease

In men with BCR, defined as elevated PSA levels following definitive treatment (either surgery or radiotherapy) and no evidence of metastatic disease on imaging, a prostate biopsy should be performed to evaluate for local recurrence before considering salvage therapy. Most guidelines discourage routine use of androgen deprivation therapy (ADT) due to the limited oncologic benefit of starting treatment at this stage; however, it is still frequently administered based on provider preference. As previously noted, XRT is advised for patients with detectable PSA levels post-RP when PSA is <0.5 ng/mL, and may be considered for high-risk cases with PSA <0.2 ng/mL. Updated guidelines also recommend combining ADT with XRT in patients exhibiting high-risk features (e.g., PSA > 0.7 ng/mL, PSADT < 6 months, grade group 4-5, seminal vesicle involvement). In these cases, expanding the radiation field to include pelvic lymph nodes may be warranted. Conversely, for patients without high-risk features, radiation alone may be appropriate. The standard duration for ADT is 4-6 months or 18-24 months based on risk factors.

Metastatic hormone sensitive

For men with metastatic hormone-sensitive disease and no history of ADT use, treatment typically involves permanent ADT in the form of regular dosing of luteinizing hormone releasing hormone (LHRH) agonists or antagonists or surgical castration (bilateral orchiectomy). These treatments remove testosterone production from the testicles which otherwise potentiates prostate cancer growth and progression. Prior to starting LHRH agonists, patients often receive treatment with a non-steroidal antiandrogen (e.g. bicalutamide) for several days beforehand to prevent symptomatic flare-ups from the temporary elevation in testosterone before levels decrease to extremely low, castrate-levels. Treatment with ADT is combined with one of several agents, each of which has high level clinical trial evidence to support their use (Table 5). The combination of ADT with an androgen receptor signaling inhibitor (E.g. abiraterone) or docetaxel is called “doublet therapy” while the combination of ADT with both an androgen receptor signaling inhibitor and docetaxel is called “triplet therapy”. Recent AUA guidelines advise against use of Docetaxel for patients undergoing XRT and ADT. The choice between treatment options is often based on the metastatic burden of the prostate cancer (high vs low). Finally, radiotherapy to the prostate itself has been shown to lengthen overall survival for patients with a low volume of metastatic disease.

Table 5: Treatments for men with metastatic prostate cancer in combination with androgen deprivation therapy

Treatment	Mechanism	Clinical setting
Abiraterone	Block production of androgens in the prostate and adrenal glands in addition to the testes	Metastatic hormone sensitive and metastatic castrate-resistant
Enzalutamide	Androgen receptor antagonist	Metastatic hormone sensitive, non-metastatic castrate-resistant, and metastatic castrate-resistant
Apalutamide	Androgen receptor antagonist	Metastatic hormone sensitive and non-metastatic castrate-resistant
Darolutamide	Androgen receptor antagonist	Non-metastatic castrate-resistant
Docetaxel	Taxane chemotherapy	Metastatic hormone sensitive and metastatic castrate-resistant
Cabazitaxel	Taxane chemotherapy	Metastatic castrate-resistant
Radiotherapy to the prostate or metastatic lesions	Radiotherapy	Metastatic hormone sensitive and low volume of metastatic disease
PARP	Inhibit repair of single-strand DNA breaks leading to double-strand breaks	Metastatic castrate-resistant with homologous recombination gene mutations
Radium-223	Intravenous alpha radiation-emitting agent that targets osteoblastic metastatic lesions in bones	Metastatic castrate-resistant with symptomatic bone metastases and no visceral metastases.
Sipuleucel-T	Autologous leukocytes sensitized to prostate cancer antigens	Metastatic castrate-resistant and asymptomatic or minimally symptomatic disease
Lutetium-177–PSMA-617	Radioligand therapy	Metastatic castrate-resistant after treatment with one androgen-receptor–pathway inhibitor and at least one taxane chemotherapy

Non-metastatic castration resistant

In men who receive hormonal therapy for biochemical recurrence and no metastatic disease, their prostate cancer invariably become resistant to ADT and can grow and progress despite castration levels of testosterone as indicated by a rise in serum PSA. Historically, these men were treated with ADT alone until metastatic disease was detected on imaging. However, the use of androgen receptor antagonists (Table 5) can improve survival and prolong time to metastatic recurrence. These patients require serial PSA measurement at three-to-six-month intervals, along with calculating the PSA doubling time to develop a treatment plan. If these patients have lower risk  (based on PSA doubling time), then they can be managed with continued ADT and active surveillance.

Metastatic castration resistant

Several options exist for men with metastatic disease and disease progression (growth or rising PSA) despite ADT (Table 5). The choice of exact treatment is dependent on previous treatments given and various other clinical scenarios. For instance, Radium-223 is only given to men with symptomatic bone metastases.

Metastasis-directed Therapy

Recent clinical trials suggest that treating patients who have a low-burden of metastatic disease (oligometastatic) with stereotactic ablative radiotherapy (SABR)/metastasis-directed therapy (MDT) may delay the need for systemic hormone therapy. However, the impact on overall survival is still being evaluated in ongoing studies. While promising, SABR/MDT should be used cautiously—preferably  within clinical trials or after carefully weighing potential benefits and risks.

Treatment adverse effect and health monitoring

The side effect profiles of various treatments for advanced prostate cancer are diverse and require careful monitoring beyond standard cancer assessments. RT can lead to urinary incontinence, erectile dysfunction, and bowel issues. ADT is often associated with increased risk of dysmetabolic syndrome, cardiovascular disease, reduced bone health, increased fracture risk, and cognitive impairment, with longer treatment duration exacerbating these side effects. ADT also leads to declines in libido due to suppression of androgen production. Abiraterone, which inhibits glucocorticoid synthesis, is typically dosed with prednisone to prevent related side effects. Familiarity with the treatments received by or ongoing treatments for patients with prostate cancer can help guide providers towards minimizing adverse effects.

Summary

Appropriate screening for prostate cancer enables early detection of a curable disease while minimizing overdiagnosis of low-risk tumors. Treatment decisions for localized prostate cancer requires careful consideration of the risks and benefits of treatment based on the individual patient and their cancer profile. Advances in therapies for metastatic prostate cancer have helped prolong the lives of many patients, but it is important to consider their impact on quality of life. By tailoring screening and treatment strategies, we can improve patient outcomes and enhance overall care.

Case Study

Prostate Cancer Case Study

Additional Resources AUA Core Curriculum: For more content on prostate cancer, please follow the links below to access the AUA Core Curriculum.  Access is free for AUA members and Medical Students qualify for a free AUA membership!  Learn more on our membership page. Prostate and Seminal Vesicle Prostate Cancer Localized and Locally Advanced Treatment Prostate Cancer Screening, Diagnosis and Risk Stratification Prostate Cancer: Advanced and Metastatic Disease Patient Education: Check out these free patient resources from the Urology Care Foundation. Early-Stage Prostate Cancer Advanced Prostate Cancer Prostate Basics

References

• Salvage Therapy for Prostate Cancer: AUA/ASTRO/SUO Guideline (2024). https://www.auanet.org/guidelines-and-quality/guidelines/salvage-therapy-for-prostate-cancer
• Prostate Cancer, Version 1.2023, NCCN Clinical Practice Guidelines in Oncology. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf
• Early Detection of Prostate Cancer: AUA/SUO Guideline (2023). https://www.auanet.org/guidelines-and-quality/guidelines/early-detection-of-prostate-cancer-guidelines
• Clinically Localized Prostate Cancer: AUA/ASTRO Guideline (2022) Endorsed by SUO. https://www.auanet.org/guidelines-and-quality/guidelines/clinically-localized-prostate-cancer-aua/astro-guideline-2022
• Advanced Prostate Cancer: AUA/SUO Guideline (Published 2020; Amended 2023). https://www.auanet.org/guidelines-and-quality/guidelines/advanced-prostate-cancer

Authors

2024

Anael S. Rizzo, MLS, BS
Los Angeles, CA
Disclosures: Nothing to disclose

Adam B. Weiner, MD
Los Angeles, CA
Disclosures: Nothing to disclose

Dharam Kaushik, MD
Houston, TX
Disclosures: Nothing to disclose

2023
Adam B. Weiner, MD
Los Angeles, CA
Disclosures: Nothing to disclose

Trushar Patel, MD
Tampa, FL
Disclosures: Nothing to disclose

2022
Adam B. Weiner, MD
Los Angeles, CA

Moben Mirza, MD
Kansas City, KS

2020
Adam B. Weiner, MD
Chicago, IL
Disclosures: Nothing to disclose

Moben Mirza, MD
Kansas City, KS
Disclosures: Nothing to disclose

2018
Moben Mirza, MD
Kansas City, KS
Disclosures: Nothing to disclose

2016
Michael Hollis, MD
Brighton, MA
Disclosures: Nothing to disclose

Jessica Kreshover, MD
Brooklyn, NY
Disclosures: Nothing to disclose

2013
Gilad Amiel, MD
Houtston, TX
Disclosures: Nothing to disclose

Martha Terris, MD
Augusta, GA
Disclosures: Nothing to disclose

Acknowledgements

Alexander Tatem, 4th year medical student at the Medical College of Georgia contributed to this review.

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