AUA2021 COURSE: Prostate Cancer Update 2021
By: William J. Catalona, MD; Douglas M. Dahl, MD; Stanley L. Liauw, MD; Stacy Loeb, MD, MSc, PhD (hon); Robert B. Nadler, MD; Russell Z. Szmulewitz, MD | Posted on: 06 Dec 2021
At the conclusion of the activity, participants will be able to:
- Cite important new publications in this field during the past year.
- Identify the relative strengths and weaknesses of the reports.
- Appraise how new studies relate to the existing state-of-the-art in clinical practice.
- Analyze whether they and their colleagues should consider changing their practice based on the new information.
Several important new publications addressed major prostate cancer (PC) topics in 2020–2021.
Up to age 76, prostate specific antigen (PSA) screening was associated with a lower all-cause mortality rate, except for men with cognitive dysfunction.1
Categories of genetic-based biomarkers include common germline single-nucleotide polymorphisms, rare germline genetic mutations (eg BRCA1/2, HOXB13), and somatic (tumor) gene expression panels (eg Oncotype Dx®, Decipher®). For PC risk assessment, a polygenic risk score incorporating 269 PC risk single-nucleotide polymorphisms is more accurate for assessing risk for PC than is the family history, which is recommended by National Comprehensive Cancer Network® guidelines.2,3 Most of the single-nucleotide polymorphisms work across races, and 50% of aggressive tumors occur in men in the top 20th percentile of the polygenic risk score.2 A study reported that polygenic risk score is associated with conversion from active surveillance (AS) to treatment.4 Rare highly penetrant germline variants (eg BRCA2, ATM) also are associated with risk, and together the common and rare variants lead to more precise estimates of the lifetime risk of PC.2,3,5 Plasma cell-free DNA may become important for managing patients with advanced PC, as it is prognostic for overall survival, selecting therapy, and response to therapy.6 It may be more helpful than repeated biopsies.
Outside the equal-access Veterans Administration (VA) system, Black men were more likely to present with metastatic disease and had correspondingly higher PC mortality rates, but these differences were not observed in the VA system.7 However, VA studies of men who were potential candidates for AS reported that Black patients were more likely to have intermediate risk disease, less likely to receive conservative management, and more likely to receive definitive therapy within 5 years.8 Most of the racial disparities appear to be due to sociodemographic factors.7 Among those managed with AS, Black men were reported to have more frequent disease reclassification and/or progression and definitive treatment but not more metastasis or higher PC-specific mortality.9 A multi-institutional AS study outside the VA system found no association of race with conversion to treatment.10 Thus, AS appears comparably safe for Black and White men.11 PSA velocity was reported to be associated with Gleason grade progression and metastases, but the thresholds were lower for Black men.12
Transperineal prostate biopsy is being increasingly adopted (in a third of urologists recently polled) to reduce the risk of sepsis (even without antibiotics) and, with fusion guidance, to provide an improved sampling of the apical and anterior regions of the prostate.13 The challenges of transperineal biopsy are patient comfort, the need for a template, increased time, overhead and difficulties with insurance coverage. Transperineal biopsy involves a substantial learning curve for where and how to achieve local anesthesia, which takes practice and experience. Currently, about half are performed under intravenous sedation.
Lymph Node Metastases
Several studies failed to find clear benefits from extended pelvic lymph node dissection, while others demonstrated a benefit associated with radiotherapy to involved pelvic nodes (see Radiotherapy section below).14-16 With the emergence of prostate-specific membrane antigen (PSMA)-positron emission tomography (PET) imaging, the management of nodal metastases may become an increasingly important issue.
Magnetic Resonance Imaging (MRI): MRI increases the accuracy of diagnosing PC but does not identify which men need treatment, and serial prostate MRI alone in patients on AS is not sufficiently accurate to reliably rule out or rule in tumor reclassification or progression.17 Biparametric MRI protocols are quicker, less expensive and more accurate than those using ultrasound plus PSA alone.18 A study of men who never had a biopsy compared standard systematic ultrasound versus MRI-targeted biopsy taking only 2–3 cores from the MRI region of concern and found that the targeted biopsy alone was noninferior to systematic biopsies.19 Over a third of MRI patients avoided a biopsy, and there were 50% fewer low-grade diagnoses. Other studies have shown that adding systematic biopsies is of value and should remain part of the process. It is not unusual to find significant cancers in the systematic cores even in areas that have a normal MRI appearance. MRI is not sufficiently accurate to substitute for surveillance biopsies but is helpful overall.20,21 Patients with high Prostate Imaging–Reporting and Data System (PI-RADS™) lesions and negative initial biopsies should have repeat MRI scans, and if the high PI-RADS abnormalities persist undergo a repeat biopsy (including peri-lesion biopsies), as nearly two-thirds of these may reveal cancer.22,23 Positive target biopsies should be counted as being only 1 positive core (ie the most extensively involved core).
PSMA PET: The PSMA PET scans (gallium and fluorine) may have a large impact on patient management because of their high sensitivity and specificity.24–28 One study reported that half of the patients with positive PSMA PET scans had a serum PSA <0.2 ng/uL.26 The most accurate platform would include the PSMA PET with MRI (rather than computerized tomography) that increases the sensitivity for high-risk tumors.28
In the FLAME trial, men receiving higher doses to MRI-defined tumor nodules had a twofold reduction in biochemical failure and no additional toxicity.29 In the POP-RT study, the treatment of pelvic lymph nodes improved biochemical control and distant-metastasis-free survival at the cost of a mild increase in late genitourinary toxicity.30 In the PROSINT trial, men receiving treatment in a single fraction or 5 fractions had similar biochemical outcomes and toxicity.31 In the postoperative setting, 3 randomized studies evaluated the role of adjuvant radiation in men with high-risk disease after prostatectomy.32–34 The largest of these (RADICALS), as well as a meta-analysis, showed that early salvage therapy when needed did not compromise outcomes and spared a significant proportion of men from unnecessary treatment.32,35 The SAKK 09/10 study demonstrated that dose escalation from 64 to 70 Gy did not improve biochemical outcomes and added toxicity.33 The EMPIRE-1 study suggested that using fluciclovine PET improved biochemical outcomes compared to conventional imaging when used to select men and to plan postoperative radiation.34 In the setting of oligo-recurrence in regional lymph nodes, the GETUG07 study demonstrated ∼50% biochemical control at 3 years’ followup with pelvic radiation and 6 months of hormonal therapy (ADT).36 In the setting of metastatic disease, a secondary analysis of the STAMPEDE trial suggested that survival is improved after prostate radiation, particularly in men with lymph node only or 3 or fewer bony metastases.37
Men with locally advanced disease account for ∼15% of patients with newly diagnosed PC and have a relatively poor cancer-specific mortality. In a prospective neo-adjuvant trial for patients with high-risk disease given either 6 months of ADT with apalutamide + abiraterone/prednisone + leuprolide vs abiraterone/prednisone + leuprolide, adding the third agent didn’t make a difference, but there was a remarkable 20% complete response or minimal residual disease rate.38 A meta-analysis of neo-adjuvant trials found that 60% of patients were without biochemical recurrence after 3 years.39 In patients who achieve a complete response/minimal residual disease, there is a large difference in the recurrence rate (8% vs 50%). Thus, in the neoadjuvant setting a robust response to ADT is a good indicator of outcomes. Oral relugolix is a luteinizing hormone-releasing hormone antagonist.40 A trial of relugolix vs leuprolide showed that relugolix achieved superior testosterone suppression and it occurred faster, whereas the cardiovascular side effects were lower. A meta-analysis also showed that cardiovascular events are more frequent with the luteinizing hormone-releasing hormone agonists than with the antagonists.41 The high cost of relugolix limits its adoption. Enzalutamide is superior to bicalutamide in Black patients, but bicalutamide can be safely used to prevent testosterone flare-ups in Black patients.42 For castrate-sensitive PC, abiraterone and apalutamide have the best results for survival, and these agents do not seem to cause a cognitive decline.43 Zoledronic acid and denosumab are approved for preventing or delaying skeletal-related events.44 Zoledronic acid may compromise renal function, whereas, denosumab may cause hypocalcemia. Osteonecrosis of the jaw occurs at approximately the same rate with both agents. Denosumab is far more expensive. In patients with castrate-resistant disease, these agents improve overall survival in addition to reducing skeletal-related events and should be used in all patients with bone metastases who are castration-resistant.45 In a study of olaparib (a PARP inhibitor used in patients with homologous DNA repair deficiency mutations such as BRCA1/2) vs abiraterone/enzalutamide (crossover), in which 30% of patients had some type of pathogenic mutation, there was a significant improvement in overall survival, especially in patients with BRCA mutations.46 Another study reported that for patients with a mutation other than BRCA, cabazitaxel had an advantage.47 A trial comparing lutetium-177-PSMA-617 (a radioligand therapy targeting PSMA) with standard care using ADT in patients who had PSMA highly expressed on their metastases, there was a highly significant survival advantage for the lutetium arm.27 This radioligand treatment is not yet U.S. Food and Drug Administration-approved. Immunotherapy has been disappointing for PC. However, a study of nivolumab plus ipilimumab for metastatic castrate-resistant PC showed a 25% response rate in the pre-chemotherapy setting with a better response rate in patients whose tumors had a high mutational burden.48 This regimen was quite toxic.
- Schoenborn NL, Sheehan OC, Roth DL et al: Association between receipt of cancer screening and all-cause mortality in older adults. JAMA Netw Open 2021; 4: e2112062.
- Darst BF, Sheng X, Eeles RA et al: Combined effect of a polygenic risk score and rare genetic variants on prostate cancer risk. Eur Urol 2021; 80: 134.
- Xu J and Isaacs WB: Incorporation of polygenic risk score into guidelines for inherited risk assessment for prostate cancer. Eur Urol 2021; 80: 139.
- Jiang Y, Meyers TJ, Emeka AA et al: Genetic factors associated with prostate cancer conversion from active surveillance to treatment. Preprint at medRxiv 2021: https://doi.org/10.1101/2021.08.30.21262305. Accessed October 18, 2021.
- Plym A, Penney KL, Kalia S et al: Evaluation of a multiethnic polygenic risk score model for prostate cancer. J Natl Cancer Inst 2021; http://doi.org/10.1093/jnci/djab058.
- Sumanasuriya S, Seed G, Parr H et al: Elucidating prostate cancer behaviour during treatment via low-pass whole-genome sequencing of circulating tumour DNA. Eur Urol 2021; 80: 243.
- Klebaner D, Travis Courtney P, Garraway IP et al: Association of health-care system with prostate cancer-specific mortality in African American and Non-Hispanic White men. J Natl Cancer Inst 2021; 113: 1343.
- Parikh RB, Robinson KW, Chhatre S et al: Comparison by race of conservative management for low-risk and intermediate-risk prostate cancers in veterans from 2004 to 2018. JAMA Network Open 2020; 3: e2018318.
- Deka R, Courtney PT, Parsons JK et al: Association between African American race and clinical outcomes in men treated for low-risk prostate cancer with active surveillance. JAMA 2020; 324: 1747.
- Cooley LF, Emeka AA, Meyers TJ et al: Factors associated with time to conversion from active surveillance to treatment for prostate cancer in a multi-institutional cohort. J Urol 2021; 206: 1147.
- Shen X, Pettaway CA and Chen RC: Active surveillance for Black men with low-risk prostate cancer. JAMA 2020; 324: 1733.
- Nelson TJ, Javier-DesLoges J, Deka R et al: Association of prostate-specific antigen velocity with clinical progression among African American and Non-Hispanic White men treated for low-risk prostate cancer with active surveillance. JAMA Netw Open 2021; 4: e219452.
- Bajeot AS, Covin B, Meyrignac O et al: Managing discordant findings between multiparametric magnetic resonance imaging and transrectal magnetic resonance imaging-directed prostate biopsy–the key role of magnetic resonance imaging-directed transperineal biopsy. Eur Urol Oncol 2021; http://doi.org/10.1016/j.euo.2021.06.001.
- Cacciamani GE, Maas M, Nassiri N et al: Impact of pelvic lymph node dissection and its extent on perioperative morbidity in patients undergoing radical prostatectomy for prostate cancer: a comprehensive systematic review and meta-analysis. Eur Urol Oncol 2021; 4: 134.
- Lestingi JFP, Guglielmetti GB, Trinh QD et al: Extended versus limited pelvic lymph node dissection during radical prostatectomy for intermediate- and high-risk prostate cancer: early oncological outcomes from a randomized phase 3 trial. Eur Urol 2021; 79: 595.
- Touijer KA, Sjoberg DD, Benfante N et al: Limited versus extended pelvic lymph node dissection for prostate cancer: a randomized clinical trial. Eur Urol Oncol 2021; 4: 532.
- Borre M: Prostate Cancer screening–the need for and clinical relevance of decision analytical models. JAMA Netw Open 2021; 4: e212182.
- Eldred-Evans D, Burak P, Connor MJ et al: Population-based prostate cancer screening with magnetic resonance imaging or ultrasonography: the IP1-PROSTAGRAM study. JAMA Oncol 2021; 7: 395.
- Klotz L, Chin J, Black PC et al: Comparison of multiparametric magnetic resonance imaging-targeted biopsy with systematic transrectal ultrasonography biopsy for biopsy-naive men at risk for prostate cancer: a phase 3 randomized clinical trial. JAMA Oncol 2021; 7: 534.
- Rajwa P, Pradere B, Quhal F et al: Reliability of serial prostate magnetic resonance imaging to detect prostate cancer progression during active surveillance: a systematic review and meta-analysis. Eur Urol 2021; http://doi.org/10.1016/j.eururo.2021.05.001.
- Zhou Z, Zhou Y, Yan W et al: Unilateral lesion detected on preoperative multiparametric magnetic resonance imaging and MRI/US fusion-guided prostate biopsy is not an appropriate indication for focal therapy in prostate cancer. Urol Oncol 2021; 39: 730 e717.
- Meng X, Chao B, Chen F et al: Followup of men with PI-RADS 4 or 5 abnormality on prostate magnetic resonance imaging and nonmalignant pathological findings on initial targeted prostate biopsy. J Urol 2021; 205: 748.
- Lahoud J, Doan P, Kim Let al: Perilesional biopsies increase detection of significant prostate cancer in men with PI-RADS 4/5 lesions: validation of the PI-RADS Steering Committee recommendation. Eur Urol 2021; 80: 260.
- Calais J, Ceci F, Eiber M et al: 18F-fluciclovine PET-CT and 68Ga-PSMA-11 PET-CT in patients with early biochemical recurrence after prostatectomy: a prospective, single-centre, single-arm, comparative imaging trial. Lancet Oncol 2019; 20: 1286.
- Pienta KJ, Gorin MA, Rowe SP et al: A Phase 2/3 prospective multicenter study of the diagnostic accuracy of prostate specific membrane antigen PET/CT with 18F-DCFPyL in prostate cancer patients (OSPREY). J Urol 2021; 206: 52.
- Cerci JJ, Fanti S, Lobato EE et al: Diagnostic performance and clinical impact of 68Ga-PSMA-11 imaging in early relapsed prostate cancer after radical therapy: a prospective multicenter study (IAEA-PSMA study). J Nucl Med 2021; http://doi.org/10.2967/jnumed.120.261886.
- Sartor O, de Bono J, Chi KN et al: Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med 2021; 385: 1091.
- Kalapara AA, Ballok ZE, Ramdave S et al: Combined utility of 68Ga-prostate-specific membrane antigen positron emission tomography/computed tomography and multiparametric magnetic resonance imaging in predicting prostate biopsy pathology. Eur Urol Oncol 2021; http://doi.org/10.1016/j.euo.2021.02.006.
- Kerkmeijer LGW, Groen VH, Pos FJ et al: Focal boost to the intraprostatic tumor in external beam radiotherapy for patients with localized prostate cancer: results from the FLAME randomized phase III trial. J Clin Oncol 2021; 39: 787.
- Murthy V, Maitre P, Kannan S et al: Prostate-only versus whole-pelvic radiation therapy in high-risk and very high-risk prostate cancer (POP-RT): outcomes from Phase III randomized controlled trial. J Clin Oncol 2021; 39: 1234.
- Greco C, Pares O, Pimentel N et al: Safety and efficacy of virtual prostatectomy with single-dose radiotherapy in patients with intermediate-risk prostate cancer: results from the PROSINT phase 2 randomized clinical trial. JAMA Oncol 2021; 7: 700.
- Parker CC, Clarke NW, Cook AD et al: Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial. Lancet 2020; 396: 1413.
- Ghadjar P, Hayoz S, Bernhard J et al: Dose-intensified versus conventional-dose salvage radiotherapy for biochemically recurrent prostate cancer after prostatectomy: the SAKK 09/10 randomized phase 3 trial. Eur Urol 2021; 80: 306.
- Jani AB, Schreibmann E, Goyal S et al: 18F-Fluciclovine-PET/CT imaging versus conventional imaging alone to guide postprostatectomy salvage radiotherapy for prostate cancer (EMPIRE-1): a single centre, open-label, phase 2/3 randomised controlled trial. Lancet 2021; 397: 1895.
- Vale CL, Fisher D, Kneebone A et al: Adjuvant or early salvage radiotherapy for the treatment of localised and locally advanced prostate cancer: a prospectively planned systematic review and meta-analysis of aggregate data. Lancet 2020; 396: 1422.
- Supiot S, Vaugier L, Pasquier D et al: OLIGOPELVIS GETUG P07, a multicenter phase II trial of combined high-dose salvage radiotherapy and hormone therapy in oligorecurrent pelvic node relapses in prostate cancer. Eur Urol 2021; 80: 405.
- Ali A, Hoyle A, Haran AM et al: Association of bone metastatic burden with survival benefit from prostate radiotherapy in patients with newly diagnosed metastatic prostate cancer: a secondary analysis of a randomized clinical trial. JAMA Oncol 2021; 7: 555.
- McKay RR, Xie W, Ye H et al: Results of a randomized phase II trial of intense androgen deprivation therapy prior to radical prostatectomy in men with high-risk localized prostate cancer. J Urol 2021; 206: 80.
- McKay RR, Berchuck J, Kwak L et al: Outcomes of post-neoadjuvant intense hormone therapy and surgery for high risk localized prostate cancer: results of a pooled analysis of contemporary clinical trials. J Urol 2021; 205: 1689.
- Shore ND, Saad F, Cookson MS et al: Oral relugolix for androgen-deprivation therapy in advanced prostate cancer. N Engl J Med 2020; 382: 2187.
- Abufaraj M, Iwata T, Kimura S et al: Differential impact of gonadotropin-releasing hormone antagonist versus agonist on clinical safety and oncologic outcomes on patients with metastatic prostate cancer: a meta-analysis of randomized controlled trials. Eur Urol 2021; 79: 44.
- Vaishampayan UN, Heilbrun LK, Monk P 3rd et al: Clinical efficacy of enzalutamide vs bicalutamide combined with androgen deprivation therapy in men with metastatic hormone-sensitive prostate cancer: a randomized clinical trial. JAMA Netw Open 2021; 4: e2034633.
- Alibhai SMH, Breunis H, Feng G et al: Association of chemotherapy, enzalutamide, abiraterone, and radium 223 with cognitive function in older men with metastatic castration-resistant prostate cancer. JAMA Netw Open 2021; 4: e2114694.
- Takvorian SU and Haas NB: Use of bone resorption inhibitors in metastatic castration-resistant prostate cancer–20 years later, and the answer is still yes. JAMA Netw Open 2021; 4: e2117159.
- Francini E, Montagnani F, Nuzzo PV et al: Association of concomitant bone resorption inhibitors with overall survival among patients with metastatic castration-resistant prostate cancer and bone metastases receiving abiraterone acetate with prednisone as first-line therapy. JAMA Netw Open 2021; 4: e2116536.
- Hussain M, Mateo J, Fizazi K et al: Survival with olaparib in metastatic castration-resistant prostate cancer. N Engl J Med 2020; 383: 2345.
- Wallis CJD, Klaassen Z, Jackson WC et al: Olaparib vs cabazitaxel in metastatic castration-resistant prostate cancer. JAMA Netw Open 2021; 4: e2110950.
- Sharma P, Pachynski RK, Narayan V et al: Nivolumab plus ipilimumab for metastatic castration-resistant prostate cancer: preliminary analysis of patients in the CheckMate 650 trial. Cancer Cell 2020; 38: 489.