AUA2022 COURSE: Prostate Cancer Update 2022
By: William J. Catalona, MD; Douglas M. Dahl, MD; Stanley L. Liauw, MD; Stacy Loeb, MD, MSc, PhD (hon); Robert B. Nadler, MD; Russell Szmulewitz, MD | Posted on: 01 Oct 2022
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 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
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.
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.
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
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.
- Surveillance, Epidemiology, and End Results Program. Prostate: tong-term trends in U.S. age-adjusted mortality rates, 1975-2019. National Cancer Institute; 2022. Accessed March 24, 2022. https://seer.cancer.gov/explorer/application.html?site=66&data_type=2&graph_type=1&compareBy=race&chk_race_1=1&hdn_sex=2&age_range=1&advopt_precision=1&advopt_show_ci=on&advopt_display=2.
- Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7-33.
- Desai MM, Cacciamani GE, Gill K, et al. Trends in incidence of metastatic prostate cancer in the US. JAMA Netw Open. 2022;5(3):e222246.
- Horton B, Alexeeff S, Prausnitz S, Avins AL, Presti J. Race-specific trends in prostate cancer screening and presentation before and after the 2012 United States Preventive Services Task Force statement. Urol Pract. 2022;9(1):64-71.
- Leapman MS, Wang R, Park H, et al. Changes in prostate-specific antigen testing relative to the revised US Preventive Services Task Force recommendation on prostate cancer screening. JAMA Oncol. 2022;8(1):41-47.
- Qiao EM, Lynch JA, Lee KM, et al. Evaluating prostate-specific antigen screening for young African American men with cancer. J Natl Cancer Inst. 2022;114(4):592-599.
- Smith J, Dodd RH, Gainey KM, et al. Patient-reported factors associated with older adults’ cancer screening decision-making: a systematic review. JAMA Netw Open. 2021;4(11):e2133406.
- Godtman RA, Kollberg KS, Pihl CG, Månsson M, Hugosson J. The association between age, prostate cancer risk, and higher Gleason score in a long-term screening program: results from the Goteborg-1 Prostate Cancer Screening Trial. Eur Urol. 2022; doi: 10.1016/j.eururo.2022.01.018.
- Clark R, Narod S. Patterns of mortality after prostate cancer: a SEER-based analysis. Presented at annual meeting of the Society of Urologic Oncology, Orlando, Florida, December 1-3, 2021.
- Cheng E, Soulos PR, Irwin ML, et al. Neighborhood and individual socioeconomic disadvantage and survival among patients with nonmetastatic common cancers. JAMA Netw Open. 2021;4(12):e2139593.
- Leapman MS, Dinan M, Pasha S, et al. Mediators of racial disparity in the use of prostate magnetic resonance imaging among patients with prostate cancer. JAMA Oncol. 2022;8(5):687-696.
- Stern N, Ly TL, Welk B, et al. Association of race and ethnicity with prostate cancer-specific mortality in Canada. JAMA Netw Open. 2021;4(12):e2136364.
- Yamoah K, Lee KM, Awasthi S, et al. Racial and ethnic disparities in prostate cancer outcomes in the Veterans Affairs Health Care System. JAMA Netw Open. 2022;5(1):e2144027.
- Loeb S, Borno HT, Gomez S, et al. Representation in online prostate cancer content lacks racial and ethnic diversity: implications for Black and Latinx Men. J Urol. 2022;207(3):559-564.
- Mouzannar A, Kuchakulla M, Blachman-Braun R, et al. Impact of plant-based diet on PSA level: data From the National Health and Nutrition Examination Survey. Urology. 2021;156:205-210.
- Loeb S, Fu BC, Bauer SR, et al. Association of plant-based diet index with prostate cancer risk. Am J Clin Nutr. 2022;115(3):662-670.
- Vettenranta A, Murtola TJ, Raitanen J, et al. Outcomes of Screening for Prostate Cancer Among Men Who Use Statins. JAMA Oncol. 2022;8(1):61-68.
- Sivanesan S, Tasken KA, Grytli HH. Association of beta-blocker use at time of radical prostatectomy with rate of treatment for prostate cancer recurrence. JAMA Netw Open. 2022;5(1):e2145230.
- Huang W, Randhawa R, Jain P, et al. Development and validation of an artificial intelligence-powered platform for prostate cancer grading and quantification. JAMA Netw Open. 2021;4(11):e2132554.
- Leapman MS, Wang R, Park HS, et al. Adoption of new risk stratification technologies within US hospital referral regions and association with prostate cancer management. JAMA Netw Open. 2021;4(10):e2128646.
- Plym A, Diossy M, Szallasi Z, et al. DNA repair pathways and their association with lethal prostate cancer in African American and European American men. JNCI Cancer Spectr. 2022;6(1):pkab097.
- Bancroft EK, Page EC, Brook MN, et al. A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study. Lancet Oncol. 2021;22(11):1618-1631.
- Pagadala MS, Lynch J, Karunamuni R, et al. Polygenic risk of any, metastatic, and fatal prostate cancer in the Million Veteran Program. Accessed April 15, 2022. https://www.medrxiv.org/content/10.1101/2021.09.24.21264093v4.full.pdf.
- Barnes DR, Silvestri V, Leslie G, et al. Breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers using polygenic risk scores. J Natl Cancer Inst. 2022;114(1):109-122.
- Eklund M, Jaderling F, Discacciati A, et al. MRI-targeted or standard biopsy in prostate cancer screening. N Engl J Med. 2021;385(10):908-920.
- Kim MM, Wu S, Lin SX, et al. Transperineal multiparametric magnetic resonance imaging-ultrasound fusion targeted prostate biopsy combined with standard template improves prostate cancer detection. J Urol. 2022;207(1):86-94.
- Patel HD, Koehne EL, Shea SM, et al. Systematic versus targeted magnetic resonance imaging/ultrasound fusion prostate biopsy among men with visible lesions. J Urol. 2022;207(1):108-117.
- Wagensveld IM, Osses DF, Groenendijk PM, et al. A prospective multicenter comparison study of risk-adapted ultrasound-directed and magnetic resonance imaging-directed diagnostic pathways for suspected prostate cancer in biopsy-naïve men. Eur Urol. 2022; doi: 10.1016/j.eururo.2022.03.003.
- Grey ADR, Scott R, Shah B, et al. Multiparametric ultrasound versus multiparametric MRI to diagnose prostate cancer (CADMUS): a prospective, multicentre, paired-cohort, confirmatory study. Lancet Oncol. 2022;23(3):428-438.
- Immerzeel J, Israel B, Bomers J, et al. Multiparametric magnetic resonance imaging for the detection of clinically significant prostate cancer: what urologists need to know. Part 4: transperineal magnetic resonance-ultrasound fusion guided biopsy using local anesthesia. Eur Urol. 2022;81(1):110-117.
- Hope TA, Calais J. PSMA PET in prostate cancer—a biomarker or a surrogate end point? Reply. JAMA Oncol. 2022;8(4):1.
- Parry MG, Nossiter J, Morris M, et al. Comparison of the treatment of men with prostate cancer between the US and England: an international population-based study. Prostate Cancer Prostatic Dis. 2022; doi: 10.1038/s41391-021-00482-6.
- Press BH, Jones T, Olawoyin O, et al. Association between a 22-feature genomic classifier and biopsy Gleason upgrade during active surveillance for prostate cancer. Eur Urol Open Sci. 2022;37:113-119.
- Jairath NK, Dal Pra A, Vince R, Jr, et al. A systematic review of the evidence for the decipher genomic classifier in prostate cancer. Eur Urol. 2021;79(3):374-383.
- Beckmann KR, Bangma CH, Helleman J, et al. Comparison of outcomes of different biopsy schedules among men on active surveillance for prostate cancer: an analysis of the G.A.P.3 Global Consortium database. Prostate. 2022;82(7):876-879.
- de la Calle CM, Shee K, Chu CE, Cowan JE, Nguyen HG, Carroll PR. Association of age with risk of adverse pathological findings in men undergoing delayed radical prostatectomy following active surveillance. Urology. 2021;155:91-95.
- Press BH, Khajir G, Ghabili K, et al. Utility of PSA density in predicting upgraded Gleason score in men on active surveillance with negative MRI. Urology. 2021;155:96-100.
- Sayyid RK, Klotz L, Benton JZ, et al. Influence of sociodemographic factors on definitive intervention among low-risk active surveillance patients. Urology. 2021;155:117-123.
- Timilshina N, Komisarenko M, Martin LJ, et al. Factors associated with discontinuation of active surveillance among men with low-risk prostate cancer: a population-based study. J Urol. 2021;206(4):903-913.
- Waisman Malaret AJ, Chang P, Zhu K, et al. Evaluating the outcomes of active surveillance in grade group 2 prostate cancer: prospective results from the Canary PASS Cohort. J Urol. 2022;207(4):805-813.
- Agochukwu-Mmonu N, Qi J, Dunn RL, et al. Patient- and surgeon-level variation in patient-reported sexual function outcomes following radical prostatectomy over 2 years: results from a statewide surgical improvement collaborative. JAMA Surg. 2022;157(2):136-144.
- Wallis CJD, Zhao Z, Huang LC, et al. Association of treatment modality, functional outcomes, and baseline characteristics with treatment-related regret among men with localized prostate cancer. JAMA Oncol. 2022;8(1):50-59.
- Perera M, Tin A, Beech B, et al. Oncologic outcomes of men with adverse pathology and biochemical persistence after radical prostatectomy. Presented at annual meeting of the Society of Urologic Oncology. Orlando, Florida, December 1-3, 2021.
- Ma TM, Romero T, Nickols NG, et al. Comparison of response to definitive radiotherapy for localized prostate cancer in Black and White men: a meta-analysis. JAMA Netw Open. 2021;4(12):e2139769.
- Kishan AU, Sun Y, Hartman H, et al. Androgen deprivation therapy use and duration with definitive radiotherapy for localised prostate cancer: an individual patient data meta-analysis. Lancet Oncol. 2022;23(2):304-316.
- Maitre P, Sood S, Pathare P, et al. Timing of Ga68-PSMA PETCT and patterns of recurrence after prostate radiotherapy: implications for potential salvage. Radiother Oncol. 2022;169:71-76.
- Crook J, Rodgers J, Pisansky T, et al. Salvage low dose rate prostate brachytherapy: clinical outcomes of a phase II trial for local recurrence after external beam radiotherapy (NRG/RTOG-0526). Int J Radiat Oncol Biol Phys. 2020;108(suppl 3):S3.
- Turchan WT, Cutright D, Wu T, et al. Hematuria following post-prostatectomy radiotherapy: incidence increases with long-term followup. J Urol. 2022;207(6):1236-1245.
- Schmidt AL, Tucker MD, Bakouny Z, et al. Association between androgen deprivation therapy and mortality among patients with prostate cancer and COVID-19. JAMA Netw Open. 2021;4(11):e2134330.
- Attard G, Murphy L, Clarke NW, et al. Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol. Lancet. 2022;399(10323):447-460.
- Lopes RD, Higano CS, Slovin SF, et al. Cardiovascular safety of degarelix versus leuprolide in patients with prostate cancer: the primary results of the PRONOUNCE randomized trial. Circulation. 2021;144(16):1295-1307.
- Spetsieris N, Boukovala M, Alafis I, et al. Abiraterone acetate plus prednisone in non-metastatic biochemically recurrent castration-naive prostate cancer. Eur J Cancer. 2021;157:259-267.
- Smith MR, Hussain M, Saad F, et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med. 2022;386(12):1132-1142.
- Marar M, Long Q, Mamtani R, Narayan V, Vapiwala N, Parikh RB. Outcomes among African American and non-Hispanic White men with metastatic castration-resistant prostate cancer with first-line abiraterone. JAMA Netw Open. 2022;5(1):e2142093.
- Sweeney C, Bracarda S, Sternberg CN, et al. Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150): a multicentre, randomised, double-blind, phase 3 trial. Lancet. 2021;398(10295):131-142.
- Denmeade SR, Wang H, Agarwal N, et al. TRANSFORMER: a randomized phase II study comparing bipolar androgen therapy versus enzalutamide in asymptomatic men with castration-resistant metastatic prostate cancer. J Clin Oncol. 2021;39(12):1371-1382.
- Powles T, Yuen KC, Gillessen S, et al. Atezolizumab with enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer: a randomized phase 3 trial. Nat Med. 2022;28(1):144-153.
- Vogelzang NJ, Beer TM, Gerritsen W, et al. Efficacy and safety of autologous dendritic cell-based immunotherapy, docetaxel, and prednisone vs placebo in patients with metastatic castration-resistant prostate cancer: the VIABLE phase 3 randomized clinical trial. JAMA Oncol. 2022;8(4):546-552.
- Schweizer MT, Sivakumar S, Tukachinsky H, et al. Concordance of DNA repair gene mutations in paired primary prostate cancer samples and metastatic tissue or cell-free DNA. JAMA Oncol. 2021;7(9):1378-1382.