AUA2021 COURSE:What's New in the Management of Hormone Naive and Castrate Resistant Prostate Cancer: A Case-Based Session for Urologists, Advanced Practice Providers and Teams
By: Judd W. Moul, MD, FACS; Lawrence I. Karsh, MD, FACS; Evan Y. Yu, MD | Posted on: 06 Dec 2021
At the conclusion of the activity, participants will be able to:
- List the 3 main advanced prostate cancer disease states (HSMPC, M0 CRPC and M1 CRPC) and be able to identify these patients in urological practice.
- Identify FDA-approved hormonal and nonhormonal therapies for use in each of these 3 disease states: HSMPC, M0 CRPC, M1 CRPC.
- Demonstrate the safe use and unique mechanism of action and side effects of new and existing agents.
- Explain the sequencing of novel therapies and be able to identify patient progression of disease by PSA, imaging, and signs and symptoms.
- Work in team care including urologists, advanced practice providers, oncology nursing, oncology pharmacy, medical oncology and radiation oncology and their support staffs.
As the course director, I have been fortunate to host a course on advanced prostate cancer at the annual AUA since 2012, and the changes over these 10 years have been nothing less than breathtaking!1 Furthermore, this may have been the most “interesting” year with regard to the COVID-19 pandemic. We were all excited to meet live in Vegas, but this did not work out and we did our course virtually. The content is available on demand from the AUA until the end of 2021 at www.aua2021.org.
In the early years, it was all about metastatic castrate resistant prostate cancer (CRPC) with multiple new therapeutic advances starting in 2010 (sipuleucel-T) followed by abiraterone and enzalutamide and a focus on bone targeted agents. Later, we expanded to cover hormone sensitive (HS) advanced disease due to the new data on docetaxel and abiraterone extending survival in new M1 patients. In 2017, we added the topic of nonmetastatic (M0) CRPC due to emerging data on use of apalutamide and enzalutamide in these men. Then in 2019, we doubled down on HS new M1 disease with emerging data that 4 agents (docetaxel, abiraterone, apalutamide and enzalutamide) all improve survival for men with new metastatic prostate cancer.
Now, in 2020 and 2021, we are going boldly into personalized molecular medicine with the addition of both hereditary and somatic testing for cancer-associated gene alterations and several therapeutic agents U.S. Food and Drug Administration (FDA)-approved in the past year to consider based on this molecular testing.
Newly Diagnosed HS M1 Prostate Cancer
Five years ago hormone naïve/HS newly diagnosed metastatic M1 prostate cancer became hot news with the release of the CHAARTED trial data in 2015 and the STAMPEDE trial results in 2016 showing a benefit of up-front docetaxel chemotherapy in new M1 disease.2,3 Primary androgen deprivation therapy (ADT) had been the only treatment for men with new M1 disease for more than three-quarters of a century. In the last few years CHAARTED and STAMPEDE taught us that adding 6 cycles of docetaxel within 4 months of starting hormone therapy/ADT resulted in a major survival benefit. For high volume disease (4 or more bone metastases and/or visceral metastases) the addition of chemotherapy resulted in a 17-month survival advantage compared to ADT alone. However, the initial publication hazard ratio generally supported a benefit of docetaxel for low volume M1 disease as well. The STAMPEDE trial confirmed the benefit of docetaxel and generally supported the use of chemotherapy for all men with new M1 disease. Median overall survival (OS) was 65 months for men randomized to receive docetaxel vs 43 months for men randomized to standard of care ADT alone. In 2018, Kyriakopoulos et al reported longer-term followup from CHAARTED confirming the benefit of docetaxel for high volume disease but not supporting up-front chemotherapy for low volume disease.4
In 2017 the LATITUDE trial showed that abiraterone added to ADT for men with new M1 disease resulted in a similar survival benefit as docetaxel.5 In 2019, we learned that both apalutamide and enzalutamide also significantly extend survival compared to traditional ADT alone.6–8 The results of TITAN (apalutamide) and ENZAMET and ARCHES (NCT02677896) (enzalutamide) were published showing robust benefits. In my mind, this is “Combined Androgen Blockade” or “Maximal Androgen Blockade” finally showing a survival benefit now using 2nd/3rd generation nonsteroidal antiandrogens.9
In TITAN, 1,052 men were randomized to traditional ADT alone vs ADT plus apalutamide (240 mg by mouth, daily).6 Ten percent received prior docetaxel, 80% had M1 disease at initial diagnosis, and 63% had high volume disease. In the final analysis, at a median followup of 44 months, 51% remained on apalutamide.10 Apalutamide conferred a 35% reduction in risk of death. This benefit was present regardless of disease volume or receipt of docetaxel. At 4 years, OS was 65% in the apalutamide arm and 51.8% in the ADT plus placebo group.
In a similar fashion, ARCHES (NCT02677896) and ENZAMET documented a similar benefit to enzalutamide in new M1 HS disease.7,8 ARCHES was the FDA registration trial and enrolled 1,150 new M1 patients receiving testosterone suppression with or without docetaxel, stratified by high or low volume disease, with men randomized to enzalutamide (574) versus placebo (576). Recently, at ESMO 2021, my Duke Cancer Institute partner, Dr. Andrew Armstrong, presented the latest trial update. As of the data cut-off of May 28, 2021, 397 (34.5%) patients remained on treatment, with a median followup of 44.6 months. The median treatment duration was 40.2 months on enzalutamide + ADT, 13.8 months on placebo + ADT, and 23.9 months for crossover patients. Enzalutamide + ADT extended survival vs placebo + ADT (HR 0.66, 95% CI 0.53–0.81; p <0.0001).
As noted earlier, these are the first trials to definitively prove the benefit of “Combined” or “Maximal” Androgen Blockade as first proposed by Labrie et al in the mid 1980s! Finally, the third generation nonsteroidal antiandrogens (being apalutamide and enzalutamide) prove beyond a reasonable doubt this long postulated concept.10
However, it is unclear if patients should receive docetaxel plus one of the oral agents or only 1 new therapy along with traditional ADT. The above noted ENZAMET trial did not confirm a survival benefit (at 3 years) to adding enzalutamide to men who received early docetaxel. Furthermore, no head-to-head comparisons allow us to determine which oral agent among the 3 is “better.” However, the key message for urologists is that traditional ADT alone for their patients with newly diagnosed M1 HS prostate cancer is not the current standard of care for the majority of men.11,12
Since 2010, multiple new agents have been approved by the FDA for M1 CRPC, including sipuleucel-T, cabazitaxel, abiraterone acetate, denosumab, enzalutamide and radium-223. Except for cabazitaxel, all of these agents are commonly available for urologists and oncologists to prescribe. The latest advances are olaparib, rucaparib, and pembrolizumab for patients with somatic or germline mutations in actionable genes implicated in advanced prostate cancer.13–16
Denosumab is prescribed at a dose of 120 mg (trade name XGEVA®) subcutaneously monthly to prevent skeletal related events in men with M1 CRPC with bone metastases.17 The FDA also approved a 60 mg dose (trade name Prolia®) subcutaneously twice a year to prevent bone loss (osteopenia and osteoporosis) in men without bone metastases who are on gonadotropin-releasing hormone (GnRH) analogue therapy for prostate cancer. We continue to remind urologists to be mindful of using supportive agents including vitamin D and calcium supplements, and monitoring for osteopenia and osteoporosis with annual dual energy x-ray absorptiometry scanning.
Sipuleucel-T is a novel immunotherapy approved by the FDA in 2010 for asymptomatic or minimally symptomatic M1 CRPC.18 The ideal patient for sipuleucel-T should have documented clinical metastases and a rising prostate specific antigen while on continuous hormonal therapy. The patient should not have bone or cancer pain requiring narcotic pain medications. In men with prostate specific antigen levels in the lowest quartile of the IMPACT trial (prostate specific antigen less than 22 ng/ml) there was a more robust OS advantage to sipuleucel-T. Specifically, the estimated 3-year survival in this group of treated patients was 62.6% compared to 41.6% for men randomized to the control arm of the study.19 At the virtual course in 2021, we also discussed the data from the PROSEED registry (1,902 patients) treated with sipuleucel-T in real-world practice between 2011–2014. In a retrospective analysis of 219 African-American men disease-matched to a Caucasian cohort, OS was 35.3 months vs 25.8 months.20 These intriguing data need to be confirmed in prospective fashion.
Abiraterone is a 17-lyase and 17-hydrolase inhibitor that blocks key pathways in the steroidal synthesis pathways leading to androgen production.21 Low dose prednisone (5 to 10 mg daily is a physiological dose) is recommended to be administered with abiraterone to help limit overproduction of aldosterone and limit the side effects of hypertension, hypokalemia and fluid retention. The FDA-approved indication for abiraterone is before or after docetaxel chemotherapy in men with M1 CRPC based on evidence from the Cougar-AA-301 and 302 clinical trials. The dose for abiraterone is 1,000 mg orally once daily in the fasted state along with low dose steroid (5 mg prednisone orally twice daily). The final analyses of both trials were reviewed, showing clinically meaningful end points of OS and radiographic progression-free survival (Cougar 302) benefits. Abiraterone is also available in a 500 mg oral dose which allows for 2 rather than 4 pills per day, which might help with compliance for some men.
Abiraterone was FDA-approved for use in men with newly diagnosed HS M1 prostate cancer in February 2018.22 Approval was based on LATITUDE (NCT01715285), a placebo controlled international clinical trial that randomized 1,199 patients with metastatic high risk disease. Patients received 1,000 mg abiraterone acetate orally once daily with 5 mg prednisone once daily (in 597) or matching placebos orally once daily (in 602). Patients in both arms received a GnRH analogue or underwent bilateral orchiectomy. The major efficacy end point was OS. Median OS was not estimable and 34.7 months in the abiraterone acetate and placebos arms, respectively (HR 0.621; 95% CI 0.509, 0.756; p <0.0001). Median duration of abiraterone use was 24 months.
Enzalutamide, a next generation androgen receptor antagonist, was FDA-approved in 2012 to treat men with disease that progressed after docetaxel based chemotherapy based on level 1 evidence from the AFFIRM trial.23 It received an expanded approved in 2014 for use before chemotherapy in the PREVAIL trial. Enzalutamide is taken orally at a dose of 160 mg daily with or without food, and unlike abiraterone it does not require prednisone. However, enzalutamide does have an approximately 1% risk of seizures associated with its use and crosses the blood-brain barrier, implicating it with some risk of falls and fatigue.
PROSPER is a phase 3, randomized, double-blind, placebo controlled study of enzalutamide in men with M0 CRPC.24 It demonstrated an approximately 2-year metastasis-free survival benefit over placebo showing that metastasis-free survival is a meaningful end point. As of July 13, 2018 enzalutamide was the second FDA-approved drug for M0 CRPC. Updated data from PROSPER in 2020 confirmed an OS benefit.25
In the setting of M1 hormone-sensitive disease, enzalutamide is also FDA-approved based on ARCHES and ENZAMET as noted earlier.
As previously noted, apalutamide, with a mechanism of action similar to enzalutamide, was the first drug for M0 CRPC approved by the FDA, which occurred in February 2018.26 The data from the SPARTAN trial showed that apalutamide delayed metastasis-free survival by about 2 years. Overall the drug was very well tolerated. Unique side effects included maculopapular rash in 24% of patients but only 5% were grade 3-4. The rash usually resolved with topical lotions, drug holiday and temporary dose reduction. Approximately 4% of patients required systemic corticosteroids. In addition, 8% of patients had decreases in thyroid hormone (considered chemical hypothyroidism) and there were no grade 3-4 adverse events The FDA did not mandate thyroid testing in the approval label. Seizure was reported in 2 patients (0.2%).
Apalutamide, as noted earlier, was also proven to extend survival in newly diagnosed HS M1 prostate cancer and final analysis of the TITAN trial showed a robust 35% improvement in OS compared to ADT alone. The TITAN trial is credited with finally proving the OS benefit of “combined androgen blockade” ending a 30+-year quest to prove this concept.
Another topic of interest related to use of abiraterone and enzalutamide/apalutamide is molecular profiling. The discovery of the AR-V7 splice variant of the androgen receptor offers an intriguing glimpse of the future of personalized medicine.27 Specifically, the response to abiraterone or enzalutamide was less robust in men who harbored this variant in circulating tumor cells. In February 2018 Genomic Health, Inc. (Redwood City, California) received FDA approval for Oncotype DX® AR-V7 Nucleus Detect™ test, a commercially available assay for AR-V7.
Radium-223 is a parenteral radiopharmaceutical that can be ordered by urologists. It is usually given in a nuclear medicine or radiation oncology department setting but many large group practices have incorporated it into their centers. It is an alpha-emitting liquid radiation product that received FDA approval in May 2013 based on results from the ALSYMPCA trial.28 Radium-223 is indicated for the treatment of patients with symptomatic M1 CRPC with bone metastases and no known visceral metastatic disease. The dose regimen is 50 kBq (1.35 microcurie) per kg body weight, given at 4-week intervals in 6 injections.
Urologists may be familiar with earlier generation beta radiopharmaceuticals such as samarium and strontium. However, radium-223 is different. It is a large molecule alpha particle and does not penetrate the bone marrow to the degree of older agents. In other words, radium-223 is much less likely to cause serious bone marrow toxicity. In addition, the use of radium-223 was associated with an OS benefit whereas the older beta-emitting radiopharmaceuticals were never proven to extend survival. For radium-223 to be associated with improved survival at least 4 monthly cycles must be administered.
Radium-223 should not be used in patients currently being treated with abiraterone/prednisone. The phase III ERA223 trial compared abiraterone/prednisone plus radium-223 vs abiraterone/prednisone plus placebo in patients with asymptomatic or mildly symptomatic chemotherapy naïve metastatic CRPC. The study was unblinded in late 2017. Bayer, the manufacturer of radium-223, reported that the unblinding followed the recommendation of an independent data monitoring committee that observed an imbalance with more fractures and deaths in patients receiving radium-223 and abiraterone/prednisone vs abiraterone alone.29
In mid 2019, darolutamide was FDA-approved for M0 CRPC based on the ARAMIS trial making this the 3rd agent approved (apalutamide, enzalutamide and darolutamide) in this disease state.30 This 3rd generation nonsteroidal oral antiandrogen prolonged metastases-free survival also by approximately 2 years compared to placebo in M0 CRPC and more recently showed an OS advantage.31 The drug has twice daily oral dosing which may be a slight disadvantage compared to enzalutamide and apalutamide but does not appear to cross the blood-brain barrier to the extent of the other 2 agents, and is reportedly less apt to cause falls and seizures and might even result in less fatigue and fractures. Darolutamide is also under study for M1 hormone-sensitive prostate cancer with the ARASENS trial. This interesting trial design compares ADT plus darolutamide plus 6 cycles of docetaxel vs ADT plus docetaxel plus placebo.
Molecular Profiling and Novel Therapeutics
Current AUA and National Comprehensive Cancer Network® guidelines recommend germline and somatic testing for men with advanced prostate cancer. About 12% of men with M1 prostate cancer will harbor actionable germline mutations and about 25% of men with CRPC will have actionable somatic mutations. Most common are BRCA, ATM, and CHEK. In 2021, there are 3 new drugs approved to treat men with actionable mutations: olaparib (Lynparza-AstraZeneca), rucaparib (Rubraca-Clovis Oncology), and pembrolizumab (Keytruda-Merck).13–16
Rucaparib is a PARP inhibitor that is approved for patients with BRCA alterations; however, the label is only in the post-docetaxel setting. Olaparib offers a survival benefit (from the PROFOUND trial) for this patient population, and does not mandate prior receipt of docetaxel chemotherapy. Pembrolizumab is tissue/site agnostic for microsatellite instability high and hypermutated solid tumors.13-16
The management of advanced prostate cancer continues to evolve in exciting and sometimes unexpected ways, and 2021 has brought further options to our patients including abiraterone, enzalutamide and apalutamide in newly diagnosed HS M1 prostate cancer as well as apalutamide, enzalutamide and darolutamide for M0 CRPC. The personalized medicine era is upon us also with approval of 3 agents for patients’ actionable germline or somatic mutations.
- Komura K, Sweeney CJ, Inamoto T et al: Current treatment strategies for advanced prostate cancer. Int J Urol 2018; 25: 220.
- Sweeney CJ, Chen YH, Carducci M et al: Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 2015; 373: 737.
- 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. Lancet 2016; 387: 1163.
- Kyriakopoulos CE, Chen YH, Carducci MA et al: Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis randomized phase III E3805 CHAARTED Trial. J Clin Oncol 2018; 36: 1080.
- 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: 338.
- Chi KN, Agarwal N, Bjartell A et al: Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med 2019; 381: 13.
- Davis ID, Martin AJ, Stockler MR et al: Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med 2019; 381: 121
- 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; 37: 2974.
- Crawford ED, Schellhammer PF, McLeod DG et al: Androgen receptor targeted treatments of prostate cancer: 35 years of progress with antiandrogens. J Urol 2018; 200: 956.
- Chi KN, Chowdhury S, Bjartell A et al: Apalutamide in patients with metastatic castration-sensitive prostate cancer: final survival analysis of the randomized, double-blind, phase III TITAN study. J Clin Oncol 2021; 39: 2294.
- Lowrance WT, Breau RH, Chou R et al: Advanced prostate cancer: AUA/ASTRO/SUO guideline PART I. J Urol 2021; 205: 14.
- Lowrance WT, Breau RH, Chou R et al: Advanced prostate cancer: AUA/ASTRO/SUO guideline PART II. J Urol 2021; 205: 22.
- Siebert AL, Szymaniak BM, Numan Y et al: Genetically informed prostate cancer treatment for metastatic disease. Urol Clin North Am 2021; 48: 365.
- LeVee A, Lin CY, Posadas E et al: Clinical utility of olaparib in the treatment of metastatic castration-resistant prostate cancer: a review of current evidence and patient selection. Onco Targets Ther 2021; 14: 4819.
- Abida W, Patnaik A, Campbell D et al: Rucaparib in men with metastatic castration-resistant prostate cancer harboring a BRCA1 or BRCA2 gene alteration. J Clin Oncol 2020; 38: 3763.
- Antonarakis ES, Piulats JM, Gross-Goupil M et al: Pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer: multicohort, open-label phase II KEYNOTE-199 study. J Clin Oncol 2020; 38: 395.
- Fizazi K, Carducci M, Smith M et al: Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 2011; 377: 813.
- Handy CE and Antonarakis ES: Sipuleucel-T for the treatment of prostate cancer: novel insights and future directions. Future Oncol 2018; 14: 907.
- Schellhammer PF, Chodak G, Whitmore JB et al: Lower baseline prostate-specific antigen is associated with a greater overall survival benefit from sipuleucel-T in the Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) trial. Urology 2013; 81: 1297.
- Higano CS, Armstrong AJ, Sartor AO et al: Real-world outcomes of sipuleucel-T treatment in PROCEED, a prospective registry of men with metastatic castration-resistant prostate cancer. Cancer 2019; 125: 4172.
- Caffo O, Veccia A, Kinspergher S et al: Abiraterone acetate and its use in the treatment of metastatic prostate cancer: a review. Future Oncol 2018; 14: 431.
- Fizazi K, Tran N, Fein L et al: Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med 2017; 377: 352.
- Scott LJ: Enzalutamide: A review in castration-resistant prostate cancer. Drugs 2018; 78: 1913.
- Hussain M, Fizazi K, Saad F et al: Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med 2018; 378: 2465.
- Sternberg CN, Fizazi K, Saad F et al: Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer. N Engl J Med 2020; 382: 2197.
- Smith MR, Saad F, Chowdhury S et al: Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med 2018; 378: 1408.
- Antonarakis ES, Lu C, Wang H et al: AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014; 371: 1028.
- Parker C, Nilsson S, Heinrich D et al: Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013; 369: 213.
- Mizokami A, Kimura G, Fujii Y et al: Considering bone health in the treatment of prostate cancer bone metastasis based on the results of the ERA-223 trial. Int J Clin Oncol 2019; 24: 1629.
- Fizazi K, Shore N, Tammela TL et al: Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med 2019; 380: 1235.
- Fizazi K, Shore N, Tammela TL et al: Nonmetastatic, castration-resistant prostate cancer and survival with darolutamide. N Engl J Med 2020; 383: 1040.