Dr. Cookson notes that in 2021, 1 in 8 men will develop prostate cancer in their lifetime, 248,530 men will be diagnosed this year, 3.1 million US men will be living with prostate cancer, every 15 minutes an American will die from prostate cancer (>93 deaths per day), and 34,130 men this year alone will die of the disease. The USPSTF recommendations have a tumultuous history with PSA screening, first noting in 2008 that they recommended against PSA screening for men >75 years old. In October 2011, there was a draft recommendation against screening in all asymptomatic men, and in May 2012, the final recommendations of Grade D for PSA screening in all symptomatic men were made official. However, in 2018, the USPSTF improved its recommendation to a Grade C PSA screening for men 55-69 years of age (based on shared decision making). The impact of the USPSTF recommendations on detection has been estimated as a 28% decrease in incident prostate cancer cases in the year following the USPSTF recommendation, including 38% decrease in low-risk cancer, 28% in intermediate-risk, and 23% in high-risk cases.
Dr. Cookson then introduced the updated AUA guidelines (2020) for advanced prostate cancer. This guideline was produced by a multidisciplinary panel with representation from the AUA, ASCO, ASTRO, and SUO, as well as a patient advocate. Their systematic review was conducted from 1998 through January 20, 2020, and 192 publications were identified through an initial search, with an additional 46 carried over from the prior AUA CPRC review. During an additional updated review, 26 studies were added to the cohort of studies comprising this guideline.
The statement of evidence rating used for the guideline is as follows:
- A (High): Very confident that the true effect lies close to that of the estimate of the effect
- B (Moderate): Moderately confident in the effect estimate, whereby the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
- C (Low): Confidence in the effect estimate is limited, whereby the true effect may be substantially different from the estimate of the effect
- C (Very Low): Very little confidence in the effect estimate, whereby the true effect is likely to be substantially different from the estimate of the effect
The guideline overview is that there are 38 guideline statements discussing early evaluation and counseling, biochemical recurrence, metastatic HSPC (M1), non-metastatic CPRC (M0), metastatic CRPC, and bone health.
As the therapeutic landscape evolves to include increasingly complex combinations of systemic therapies with or without local therapies, advances in imaging, and germline and somatic testing, treating men with advanced prostate cancer is increasingly one that must embrace multidisciplinary management approaches. This team includes the urologist, medical oncologist, radiation oncologist, pathologist, genetic counselor, and palliative care specialists. Management of patient’s symptoms and quality of life are of great concern to the patients and their families. Physicians caring for patients with advanced disease should manage symptoms such as pain, urinary symptoms, and sexual function, as well as side effects of treatment. The remainder of this article will highlight the guidelines and the evidence to support them.
With regards to evaluation and counseling, in patients with suspicion of advanced prostate cancer and no prior histologic confirmation, clinicians should obtain tissue diagnosis from the primary tumor or site of metastases when clinically feasible (Clinical Principle). Clinicians should discuss treatment options with advanced prostate cancer patients based on life expectancy, comorbidities, preferences, and tumor characteristics. Patient care should incorporate a multidisciplinary approach when available (Clinical Principle). Additionally, clinicians should optimize pain control or other symptom support in advanced prostate cancer patients and encourage engagement with professional or community-based resources, including patient advocacy groups (Clinical Principle).
For biochemical recurrence without metastatic disease, clinicians should inform patients with PSA recurrence after exhaustion of local therapy regarding the risk of developing metastatic disease and follow such patients with serial PSA measurements and clinical evaluation. Clinicians may consider radiographic assessments based on overall PSA and PSA kinetics (Clinical Principle). In patients with PSA recurrence after exhaustion of local therapy who are at higher risk for the development of metastases (e.g., PSADT < 12 months), clinicians should perform periodic staging evaluations consisting of cross-sectional imaging (CT, MRI) and technetium bone scan (Clinical Principle).
In the hormone-sensitive setting, PSA recurrence almost always precedes the clinical detection of metastases. This often involves serial PSA measurements, clinical evaluation, and staging evaluations. Clinicians may utilize novel PET-CT scans in patients with PSA recurrence after failure of local therapy as an alternative to conventional imaging or in the setting of negative conventional imaging (Expert Opinion):
For patients with a rising PSA after local therapy and no demonstrated metastatic disease by conventional imaging, clinicians should offer an observation or clinical trial enrollment (Clinical Principle). ADT should be routinely initiated in this population (Expert Opinion), however, if ADT is initiated in the absence of metastatic disease, intermittent ADT may be offered in lieu of continuous ADT (Conditional Recommendation, Grade B).
With regards to patients with metastatic hormone-sensitive prostate cancer (mHSPC), clinicians should assess if a newly diagnosed mHSPC patient is experiencing symptoms from metastatic disease at the time of presentation to guide discussions of prognosis and further disease management (Moderate Recommendation; Evidence Level: Grade B). Additionally, clinicians should obtain a baseline PSA and serial PSAs at three- to six-month intervals after initiation of ADT in mHSPC patients and consider periodic conventional imaging (Clinical Principle). In patients with mHSPC, regardless of age and family history, they should be offered genetic counseling or germline testing (Expert Opinion). This panel should include genes influencing homologous recombination repair, as follows:
Clinicians should offer ADT with either LHRH agonists or antagonists or surgical castration for these men (Strong Recommendation, Grade B). In patients with metastatic hormone-sensitive prostate cancer, clinicians should offer continued ADT in combination with either androgen pathway directed therapy (abiraterone plus prednisone, apalutamide, enzalutamide) or chemotherapy (docetaxel) (Strong Recommendation, Grade A). This recommendation is based on the treatment effect seen when ADT is combined with docetaxel (CHAARTED,1 STAMPEDE ),2 abiraterone plus prednisone (LATITUDE,3 STAMPEDE),4 apalutamide (TITAN),5 or enzalutamide (ARCHES,6 ENZAMET7). Clinicians should not offer first generation antiandrogens (bicalutamide, flutamide, nilutamide) in combination with LHRH agonists in patients with mHSPC, except to block testosterone flare (Strong Recommendation; Evidence Level: Grade A). Furthermore, clinicians should not offer oral androgen pathway directed therapy (e.g., abiraterone acetate plus prednisone, apalutamide, bicalutamide, darolutamide, enzalutamide, flutamide, nilutamide) without ADT for patients with mHSPC (Expert Opinion).
With regards to treatment of the primary tumor, Dr. Cookson notes that the STAMPEDE arm H clinical trial assessed the efficacy of radiotherapy to the primary in M1 disease.8 This study randomized 2,061 to either standard systemic treatments (ADT +/- chemotherapy) versus standard systemic treatments (ADT +/- chemotherapy) plus radiotherapy to the primary. There were 819 (40%) men that had a low metastatic burden, 1,120 (54%) had a high metastatic burden, and the metastatic burden was unknown for 122 (6%). Radiotherapy improved failure-free survival (HR 0.76, 95% CI 0.68-0.84) but not OS (HR 0.92, 95% CI 0.80-1.06). In a prespecified subgroup analysis, patients receiving radiotherapy to the prostate among patients with low metastatic burden, there was a significant improvement in OS (HR 0.68, 95% CI 0.52-0.90). For surgery in this disease space, the SWOG 1802 trial (Randomized, Phase III Trial of Standard Systemic Therapy (SST) or SST Plus Definitive Treatment of the Primary Tumor in Metastatic Prostate Cancer) continues to accrue patients.
Dr. Cookson notes that men with a rising PSA but no visible metastatic disease on conventional imaging despite castration represent a uniquely distinct disease state. Serial PSAs are typically performed every 3-6 months, and conventional imaging every 6-12 months. In M0 CRPC patients, clinicians should obtain serial PSA measurements at three- to six-month intervals, and calculate a PSADT starting at the time of development of castration-resistance (Clinical Principle). Clinicians should assess M0 CRPC patients for development of metastatic disease using conventional imaging at intervals of 6 to 12 months (Expert Opinion). Until recently, there were no specific agents specifically FDA approved for the treatment of men with M0 CRPC, however three androgen receptor antagonists successfully prolonged MFS when compared to placebo in men on continued ADT in this setting: apalutamide (SPARTAN),9 darolutamide (ARAMIS),10 and enzalutamide (PROSPER)11. Additionally, recently presented at the ASCO 2020 virtual annual meeting, all three studies have now showed overall survival benefit.12-14 Based on these trials, clinicians should offer apalutamide, darolutamide, or enzalutamide with continued ADT to M0 CRPC patients at high risk for developing metastatic disease (PSADT ≤10 months) (Strong Recommendation; Evidence Level Grade A). Clinicians may recommend observation with continued ADT to M0 CRPC patients, particularly those at lower risk (PSADT >10 months) for developing metastatic disease (Clinical Principle). Furthermore, clinicians should not offer systemic chemotherapy or immunotherapy to M0 CRPC patients outside the context of a clinical trial (Clinical Principle).
Over the last 15 years, there has been tremendous advancement in the mCRPC disease space. In mCRPC patients, clinicians should assess the extent of metastatic disease using conventional imaging at least annually or at intervals determined by lack of response to therapy (Expert Opinion). Additionally, they should offer germline and somatic tumor genetic testing to identify DNA repair deficiency mutations and microsatellite instability status that may inform prognosis and counseling regarding family risk as well as potential targeted therapies (Expert Opinion). Dr. Cookson notes that since the approval of docetaxel, there have been 10 additional agents that show either an overall or metastases-free survival benefit (M0) and are now FDA approved on the bases of randomized controlled trials. These agents now include those directed at the androgen receptor, androgen production, chemotherapy, radionuclide therapy, and immunotherapy:
- Abiraterone acetate + prednisone
In newly diagnosed mCRPC patients, clinicians should offer continued ADT with abiraterone acetate plus prednisone, docetaxel, or enzalutamide (Strong Recommendation; Evidence Level: Grade A [abiraterone acetate plus prednisone and enzalutamide]/B [docetaxel]).
Both enzalutamide (PREVAIL)15 and abiraterone + prednisone (COU-AA-302)16 showed survival benefit in the pre-chemotherapy patients. Both agents also showed benefit in the post-chemotherapy setting: enzalutamide (AFFIRM)17 and abiraterone (COU-AA-301).18 In 2004, docetaxel was approved as first-line chemotherapy for mCRPC based on a 24% reduction in death compared to mitoxantrone in the TAX-327 study.19
In mCRPC patients who are asymptomatic or minimally symptomatic, clinicians may offer sipuleucel-T (Conditional Recommendation; Evidence Level: Grade B), based on results of the IMPACT trial noting that Sipuleucel-T had 22% reduction in mortality for asymptomatic or minimally symptomatic men with mCRPC who were pre-chemotherapy.20 Clinicians should offer radium-223 to patients with symptoms from bony metastases from mCRPC and without known visceral disease or lymphadenopathy >3cm (Strong Recommendation; Evidence Level: Grade B). This recommendation is based on the ALSYMPCA trial showing that patients receiving radium-223 had a significant survival benefit.21 In mCRPC patients who received prior docetaxel chemotherapy with or without prior abiraterone acetate plus prednisone or enzalutamide for the treatment of CRPC, clinicians may offer cabazitaxel (Conditional Recommendation; Evidence Level: Grade B). In mCRPC patients who received prior docetaxel chemotherapy and abiraterone acetate plus prednisone or enzalutamide, clinicians should recommend cabazitaxel rather than an alternative androgen pathway directed therapy (Strong Recommendation; Evidence Level: Grade B). These recommendations are based on patients in the TROPIC study having a 30% survival benefit among patients receiving secondary line cabazitaxel.22
Much attention has recently been directed towards the impact of DNA repair gene alterations found in patients with mCRPC. Up to 23% of these patients harbor DDR alterations, with 8% harboring DDR germline mutations. Among these mutations, BRCA2 is the most frequently altered (12.7%), and alterations in these genes are expected to confer sensitivity to PARP inhibitors, suggesting that nearly 20% of heavily pre-treated mCRPC patients may potentially benefit from this therapy. Clinicians should offer a PARP inhibitor to patients with deleterious or suspected deleterious germline or somatic homologous recombination repair gene-mutated mCRPC following prior treatment with enzalutamide or abiraterone acetate, and/or a taxane-based chemotherapy. Platinum based chemotherapy may be offered as an alternative for patients who cannot use or obtain a PARP inhibitor (Moderate Recommendation; Evidence Level: Grade C). In patients with mismatch repair deficient or microsatellite instability high mCRPC, clinicians should offer pembrolizumab (Moderate Recommendation; Evidence Level: Grade C). Based on the 2020 publication of the PROfound study, patients treated with olaparib had a median PFS of 7.4 months compared to 3.6 months for the control group,23 leading to FDA approval. Of note, rucaparib is also FDA approved for deleterious BRCA mutations based on the TRITON2 study.24
In advanced prostate cancer patients at high fracture risk due to bone loss, clinicians should recommend preventative treatments with bisphosphonates or denosumab and referral to physicians who have familiarity with the management of osteoporosis when appropriate (Clinical Principle). Finally, clinicians should prescribe a bone-protective agent (denosumab or zoledronic acid) for mCRPC patients with bony metastases to prevent skeletal related events (Moderate Recommendation, Grade B). The recent publication of the ERA-223 trial25 showed that the addition of radium-223 to abiraterone-prednisone was associated with increased rates of fractures as compared to abiraterone-prednisone alone and no improvement in symptomatic skeletal event-free survival, and thus there is now regulatory guidance to avoid abiraterone in combination with radium-223. However, early results from the PEACE-3 trial suggest that use of osteoclast-targeted agents may reduce fractures in men receiving radium-223 from mCRPC.
Dr. Cookson concluded with several key areas of future research that need to be emphasized to improve clinical care and provide a path to better patient outcomes with advanced prostate cancer, including integration of multidisciplinary care, advanced PET imaging, theranostics, biomarkers, and other systemic therapies. As follows is a summary figure highlighting the current landscape of prostate cancer in 2021:
Presented by: Michael Cookson, MD, MMHC, Professor, and Chairman, Department of Urology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md during the 85th Annual Southeastern Section of the American Urological Association, April 23-24, 2021
- Kyriakopoulos CE, Chen YH, Carducci MA, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: Long-term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol2018 Apr 10;36(11):1080-1087.
- James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. 2016;387(10024):1163-1177.
- Fizazi K, Tran N, Fein L, et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 2017;377(4):352-360.
- James ND, de Bono JS, Spears MR, et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Engl J Med. 2017;377(4):338-351.
- Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med2019 Jul 4;381(1):13-24.
- Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy with Enzalutamide or Placebo in Men with Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol.2019 Nov 10;37(32):2974-2986.
- Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N Engl J Med2019 Jul 11;381(2):121-131.
- Parker CC, James ND, Brawley CD, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. 2018;392(10162):2353-2366.
- Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med2018;378(15):1408-1418.
- Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic castration-resistant prostate cancer. N Engl J Med. 2019;380(13):1235-1246.
- Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med.2018 Jun 28;378(26):2465-2474.
- Sternberg CN, Fizazi K, Saad F, et al. Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med. 2020 Jun 4;382(23):2197-2206.
- Smith MR, Saad F, Chowdhury S, et al. Apalutamide and Overall Survival in Prostate Cancer. Eur Urol. 2021 Jan;79(1):150-158.
- Fizazi K, Shore N, Tammela TL, et al. Nonmetastatic, Castration-Resistant Prostate Cnacer and Survival with Darolutamide. N Engl J Med.2020 Sep 10;383(11):1040-1049.
- Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med2014;371(5):424-433.
- Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368(2):138-148.
- Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012;367:1187-1197.
- de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005.
- Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med2004;351:1502-1512.
- Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med2010;363(5):411-422.
- Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med2013;369(3):213-223.
- de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A randomised open-label trial. Lancet2010;376(9747):1147-1154.
- de Bono J, Mateo J, Fizazi K, et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med2020 May 28;382(22):2091-2102.
- Abida W, Patnaik A, Campbell D, et al. Rucaparib in Men with Metastatic Castration-Resistant Prostate Cancer Harboring a BRCA1or BRCA2Gene Alteration. J Clin Oncol 2020 Nov 10;38(32):3763-3772.
- Smith M, Parker C, Saad F, et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): A randomized, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol2019 Mar;20(3):408-419.