Learning Objective

At the conclusion of the activity, participants will be able to explain the research and clinical publications from the past year on prostate cancer concerning risk stratification, screening, and biopsy methods.

Statistics and Epidemiology

During the PSA screening era, the incidence of metastatic prostate cancer decreased strikingly (4%-5% presented with metastases) and the prostate cancer-specific mortality rate decreased by 53%.¹ Currently, 71%-73% of new cases present with clinically localized disease, with a 5-year survival rate of 96%-98%.² Following the 2012 USPSTF (U.S. Preventive Services Task Force) grade D recommendation against prostate cancer screening, in men younger than 70 years old, PSA screening, biopsy, and overall prostate cancer detection rates significantly decreased, while the rates of metastatic disease significantly increased in all races and age groups.^3,4 After the USPSTF’s 2018 upgrade to grade C, there has been an increase in PSA testing across all age groups—ironically, mostly in men aged 70-89 years.⁵ In young Black men, PSA screening was associated with a lower rate of metastases and prostate cancer mortality.⁶ Older adults’ ingrained beliefs about screening may run counter to guideline concepts.⁷ The higher Gleason scores in older men should be considered when counseling patients.⁸ Some are suggesting that Gleason grade group (GG) 1 should not be called “cancer;” however, most prostate cancer deaths occur in men initially diagnosed with low-grade disease.⁹

Socioeconomic status accounts for most racial prostate cancer mortality disparities.^10–12 Black men who receive primary definitive treatment have a lower risk of metastases.¹³ Online information about prostate cancer lacks racial and ethnic diversity.¹⁴

More plant-based consumption and physical activity are associated with a lower risk of elevated PSA¹⁵ and fatal prostate cancer.¹⁶ Statin use does not compromise PSA screening.¹⁷ Nonselective beta-blocker use at the time of radical prostatectomy is associated with less treatment for prostate cancer recurrence.¹⁸

Risk Stratification, Screening, and Biopsy

An artificial intelligence platform was able to detect, grade, and quantify prostate cancer with high accuracy and less interobserver variability.¹⁹ MRI and genomic testing have increased the proportion of patients receiving observation.²⁰ Altered DNA damage response is an important mechanism for aggressive prostate cancer in men of all races.²¹ The most important germline variants are pathogenic mutations of BRCA2. Lynch syndrome predisposes to various cancers, and MSH2 and MSH6 carriers have a higher prostate cancer incidence and more clinically significant disease.²² Common genetic variants individually conferring little risk for prostate cancer but combined in a “polygenic score” can confer substantial risk for prostate cancer, including aggressive disease, across ancestry groups²³ and can help further stratify the risks due to BRCA1/2 mutations.²⁴

MRI-targeted plus systematic biopsies detect more significant and less insignificant prostate cancer.^24–28 Multiparametric ultrasonography (an office procedure) compares favorably to MRI;²⁹ however, both miss some cancers detected by the other. Risk calculators provide additional information.²⁸ MRI-targeted transperineal biopsy plus systematic biopsies reduce infections (even without antibiotics) and may be advantageous for sampling anterior and apical lesions.³⁰ 68-Ga prostate-specific membrane antigen (PSMA) positron emission tomography (PET) has a sensitivity of 40% and specificity of 95% for pelvic node metastasis in intermediate -
and high-risk prostate cancer.³¹

Active Surveillance

Active surveillance rates are lower in the U.S. than in England.³² A 22-feature genomic classifier plus clinical variables outperformed the clinical model and correlated with biopsy upgrading on active surveillance.³³ This classifier provides independent prognostic value in all studies and settings with improved discrimination.³⁴ Men who had annual surveillance biopsies are more likely to be treated, with no difference in upgrading. Frequent biopsies may deter some men from continuing active surveillance despite their having no evidence of tumor progression.³⁵ In active surveillance, a confirmatory biopsy should be performed within 1 year. Men with a negative MRI or negative surveillance biopsies remain on surveillance longer. Older men require closer monitoring.³⁶ PSA density is important in discriminating the risk of upgrade among men on active surveillance with a negative MRI scan.³⁷ Most active surveillance patients eventually undergo delayed treatment, depending considerably on sociodemographic factors.^38,39 Active surveillance is increasing for low- to intermediate-risk disease. A comparison of GG1 and GG2 patients found no difference in reclassification, but GG2 patients had more treatment without reclassification, and there was no difference in biochemical recurrence at 3 years.⁴⁰

Radical Prostatectomy

An evaluation of surgeon radical prostatectomy volume and postoperative potency ranged from 3% to 44% at 24-month follow-up with no correlation with case volume.⁴¹ Treatment-related regret is greater after prostatectomy than for surveillance or radiotherapy, and is strongly tied to expectations of efficacy and side effects.⁴² In patients with nodal invasion and PSA persistence after prostatectomy, the 5- and 10-year prostate cancer-specific survival probabilities are 89% and 68%, respectively.⁴³ The low sensitivity of PSMA PET scans for lymph node metastases (˜40%) argues for lymphadenectomy or treating the pelvic nodes with radiotherapy in men at high risk for involvement.

Focal Therapy

A meta-analysis of focal therapies suggests that photodynamic therapy and high-intensity focused ultrasound are the most promising and are well tolerated; however, long-term data are lacking.

Radiotherapy

Black men enrolled in randomized clinical trials present with more aggressive disease but have better outcomes with definitive radiotherapy.⁴⁴ A hydrogel implant may be placed between the prostate and rectum to reduce the risk of post-radiotherapy rectal complications, but the clinical differences are marginal. An analysis of a randomized trial comparing 3 different radiotherapy fractionation schemes showed similar outcomes with no difference by risk category.

For men undergoing radiotherapy, erectile dysfunction was worse and hot flashes were more frequent with luteinizing hormone-releasing hormone (LHRH) agonist, while breast symptoms were more common with the antiandrogen.⁴⁵ A prospective comparison of radiotherapy with dual agent androgen-deprivation therapy (ADT) with bicalutamide plus either an LHRH agonist or a 5alpha-reductase inhibitor (5ARI) revealed more breast symptoms but better sexual function in the 5ARI group. Biochemical outcomes did not appear compromised with 5ARI use.

The patterns of recurrence as defined by a Ga-PSMA PET scan in men with biochemical failure after radiotherapy revealed that 91% of scans showed uptake, and 57% were felt to be amenable to salvage therapy.⁴⁶ Brachytherapy is an option for men with isolated local recurrence after radiotherapy. With a follow-up of 6.7 years, freedom from recurrence was 68% at 5 years and 46% at 10 years, and the 10-year overall survival was 70%. Subsequent local failure was rare, and 19% developed distant metastases (this study previously reported a grade 3 rate of late gastrointestinal or genitourinary toxicity of ˜15%).⁴⁷ Hematuria after salvage radiotherapy occurred in 45% of patients at 8 years of follow-up, and 15% required intervention beyond cystoscopy. Most cases were self-limited, although 31% had recurrent episodes.⁴⁸

Advanced Disease

ADT is not associated with decreased mortality from SARS-CoV-2 infection.⁴⁹ Abiraterone plus a glucocorticoid (Abi/Pred) and 2 years of ADT is a new standard treatment for men with localized high-risk prostate cancer receiving radiotherapy.⁵⁰ A prospective, randomized study of cardiovascular risk with degarelix vs leuprolide for 1 year revealed no difference in cardiovascular outcomes.⁵¹ Apalutamide plus Abi/Pred delays time to PSA rise during the off-period of intermittent ADT.⁵² Docetaxel plus ADT with an LHRH agonist or antagonist should be further intensified with darolutamide in metastatic hormone-sensitive prostate cancer.⁵³ Black men have improved overall survival with Abi/Pred.⁵⁴ Cabazitaxel is superior to treatment with a second androgen receptor inhibitor.⁵⁵

In patients with metastatic castrate-resistant prostate cancer (mCRPC), if the tumor cells express PSMA on their surfaces, Lu177-PSMA-617 may be a more effective therapy than switching to another hormonal therapy or to cabazitaxel (65% vs 37% PSA-response rate). Dual inhibition of the Akt serine/threonine kinase family (AKT) and the androgen receptor can modestly improve outcomes. Further studies ongoing with AKT inhibitors need to have the P10 status or the tumor determined ahead of time. Patients should have their primary or metastatic tumor sequenced.⁵⁵ Bipolar androgen therapy may resensitize mCRPC to ADT, and there is an advantage to using bipolar androgen therapy first.⁵⁶

Immunotherapy with atezolizu­mab⁵⁷ or an autologous dendritic cell-based vaccine is unlikely to work in unselected mCRPC patients.⁵⁸ Atezolizumab may work if there is an immune signature in the tumor (occurs rarely); however, it may work in Lynch syndrome patients.⁵⁷

There is a population of androgen-independent cells in the prostatectomy specimen.⁵⁹ Genomic sequencing of the primary tumor usually is concordant with cell-free DNA or metastatic sample and may provide useful information, eg for Lynch, P10 loss, or AKT variants, ie it might have therapeutic implications.