An Update on Nonmetastatic Castration-Resistant Prostate Cancer

Androgen deprivation therapy (ADT) is the backbone of therapy for advanced prostate cancer patients who have failed primary interventional therapy.  Most of these patients will develop, through a potential multitude of resistance mechanisms, neoplastic cellular progression, and proliferation which subsequently leads to PSA relapse.2 Castration-resistant prostate cancer (CRPC), a rising PSA with castrate levels of testosterone alongside no radiographic imaging findings with conventional imaging (CT/Bone scans) are designated as non-metastatic (nmCRPC), or sometimes as M0CRPC.

The US annual incidence of nmCRPC has not been accurately established. The metastatic castration-resistant prostate cancer (mCRPC) patient population evolves from patients initially diagnosed metastatic hormone-sensitive prostate cancer (mHSPC), possibly ranging from 4-6 % of the approximate 160,000 newly diagnosed US patients, yet this same group of patients represents a disproportionally higher contribution the percentage of mCRPC patients. That said, most would agree that the majority of eventual mCRPC patients herald from the PSA relapse disease state. Large data registries and retrospective observational studies of nmCRPC have correlated higher grade International Society of Urological Pathology (ISUP) stage, and a more rapid PSA doubling time to both earlier onset on nmCRPC as well as the development of metastasis.18 Prior to 2018, there was no level one evidence FDA-approved therapy for nmCRPC. Hence, most nmCRPC patients were managed expectantly or with second-line (vintage) hormonal manipulations, e.g. first generation lutamides, estrogens, steroids, or ketoconazole.

At ASCO GU, 2018,  two landmark studies reported their results  from their randomized, double-blind, placebo-controlled, phase III global trials: SPARTAN (A Study of Apalutamide (ARN-509) in Men With Non-Metastatic Castration-Resistant Prostate Cancer) and PROSPER (Safety and Efficacy Study of Enzalutamide in Patients With Nonmetastatic Castration-Resistant Prostate Cancer) trials. 3,7 In both of these placebo-controlled studies, next-generation androgen receptor inhibition, utilizing either apalutamide or enzalutamide, extended metastasis-free survival (MFS) by approximately 2 years (median) when added to ADT in men with documented nmCRPC and whose  PSA doubling times of <10 months were confirmed.3,7 These trial results led to the FDA approvals of apalutamide (ERLEADA™) and enzalutamide (XTANDI®) in 2018, a new regulatory endpoint had been accepted by the FDA, metastasis-free survival (MFS), and an unmet need of therapy, see index case 1 AUA CRPC guidelines, had now been answered. 3,4,7,8

The efficacy of enzalutamide has been well established for CRPC patients and assuredly, there are numerous ongoing trials further investigating both apalutamide and enzalutamide throughout the prostate cancer disease continuum.4 As a result of these trials, as well as next-generation imaging (NGI) techniques, which improve our diagnostic accuracy and acumen, with modalities such as positron-emission tomography (PET) with targeted radiotracers, e.g., 68Ga-labelled prostate specific membrane antigen (PSMA), C-11 choline, and  F-18 fluciclovine, these NGI techniques have demonstrated higher sensitivity and arguably enhanced accuracy for the detection of bone and soft tissue metastases compared with conventional technetium-99m bone scans, computed tomography (CT), and magnetic resonance imaging (MRI).13,14, 4 Consequently, some CRPC patients who would have been categorized as non-metastatic on conventional imaging will be classified as M1 on NGI. This may be the case for many patients within the SPARTAN and PROSPER trials, especially given the inclusion criteria for a rapid PSA doubling time. Nonetheless, like all prior CRPC phase III trials which have led to therapeutic approvals, conventional imaging was and still remains the gold standard; however, the duration of this imaging ‘gold standard’ may be soon approaching obsolescence.

Additional data on the efficacy of apalutamide and enzalutamide have been made available since their respective NEJM publications of their results from both SPARTAN and PROSPER. At ASCO GU this year, researchers reported that apalutamide significantly delayed time to further progression or death on subsequent therapy after patients stopped treatment because of disease progression (HR, 0.50 vs. patients who stopped placebo; 95% CI, 0.39-0.63; P < .0001).23 Enzalutamide, for its part, induced PSA responses (defined as at least a 50% decrease in baseline PSA) in more than 90% of patients in PROSPER, and PSA response was associated with a decreased risk of bowel, hormonal, and urinary symptoms.17 Enzalutamide also significantly delayed symptom worsening, pain progression, and declines in functional status,21 and also significantly lowered the risk of metastasis or death regardless of specific treatment history (surgery, radiation, or bone-targeting therapy).19

The overall survival (OS) benefit from these approved nmCRPC therapies is awaiting more death events before an OS endpoint of comparison to the respective placebo-controlled treatment arms can be analyzed; hopefully, we may have an interpretation of the OS findings before 2020.

Many nmCRPC patients are elderly, however one defines ‘elderly’, with the median age of enrolled patients on the trials being  in their mid-70s, and thus many will have attendant comorbidities  which augurs that the safety and tolerability of nmCRPC therapy must be an important concern in an ostensibly asymptomatic population, albeit for the effects of chronic ADT.. Both apalutamide and enzalutamide in addition to ADT may increase the risk of fatigue, falls, and fractures.4,6,7 Also reported recently, an analysis of all four phase 3, placebo-controlled trials of enzalutamide in men with CRPC (PROSPER, PREVAIL, AFFIRM, and 9785-CL-0232) linked enzalutamide with a two to three-fold higher rates of falls (9.1%) and fractures (10.2%) versus placebo.20

Enzalutamide and apalutamide are associated with an increase in the risk of certain cardiovascular events. In the aggregate study of the four enzalutamide trials, this medication was associated with a low incidence of treatment-emergent ischemic heart disease and cardiac death.20 Although rates were low (2.6% and 0.4%, respectively), they were two to four times higher than in the placebo group.20 Finally, in SPARTAN, apalutamide was associated with an increase in all-grade and grade 3-4 hypertension, and four patients who received apalutamide died of myocardial infarction, cardiorespiratory arrest, or cerebral hemorrhage, versus only one comparable death in the placebo group.7,22

These data are not surprising—ADT can cause or exacerbate cardiovascular disease,11 and augmenting anti-androgen therapy can intensify this risk.7,12 Rates of major adverse cardiovascular events on these treatments will likely remain low but may be higher outside the carefully controlled settings of clinical trials. Discussing the benefits and risks of next-generation antiandrogen therapy with patients, ensuring initial and ongoing cardiometabolic monitoring, and educating and referring patients to resources to help them implement risk-reduction measures (dietary changes, exercise, and optimization of care for comorbid cardiovascular disease, diabetes, or the metabolic syndrome) are essential to the minimization of complications.  On an individual patient basis, attempts can be made to balance and assess performance status, frailty, and comorbidity burdens with regard to their risk of disease progression.

Monitoring treatment response is nmCRPC is predicated upon PSA response, patient tolerability and imaging progression.  PSA is a downstream biomarker effect of androgen receptor signaling and an indirect indicator of tumor AR signaling activity, but a decline or rise in PSA may not always correlate with tumor cell response, especially in poorly differentiated tumors.13

Hence, we need additional measures and predictors of treatment response. Researchers are evaluating histologic, molecular, and genomic data for this purpose and it is certainly hoped that future data might better inform our treatment selection, sequencing, and intensity of monitoring based on the risk of relapse or progression. One approach is to use “molecularly detectable residual disease”—that is, circulating tumor material.13

Finally, only a few trials of next-generation antiandrogen therapies for nmCRPC have utilized an active comparator, which has drawn criticism from some reviewers.10 As we continue to develop and hone treatments for high-risk nmCRPC, we can expect trials with active comparators and those that combine next-generation anti-androgen inhibition with highly targeted treatments guided by NGI. I look forward to reviewing and sharing these findings as part of the nmCRPC Center of Excellence.

Written by: Neal Shore, MD, Medical Director of the Carolina Urologic Research Center, Atlantic Urology Clinics, Myrtle Beach, South Carolina

Published Date: March 4th, 2019

References
1. Scher HI, Solo K, Valant J, et al. Prevalence of prostate cancer clinical states and mortality in the United States: estimates using a dynamic progression model. PLoS One. 2015;10:e0139440.
2. Dai C, Heemers H, Sharifi N. Androgen signaling in prostate cancer. Cold Spring Harb Perspect Med 2017;7(9):a030452-a030452.
3. Smith MR, Saad F, Oudard, et al. Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: exploratory analyses by baseline prostate-specific antigen doubling time. J Clin Oncol. 2013;31(30):3800-3806.
4. Smith MR. Progress in nonmetastatic prostate cancer. N Engl J Med. 2018 Jun 28;378(26):2531-2532.
5. Alpajaro SIR, Harris JAK, Evans CP. Non-metastatic castration-resistant prostate cancer: a review of current and emerging medical therapies. Prostate Cancer Prostatic Dis. 2019 Mar;22(1):16-23.
6. Smith MR, Saad F, Chowdhury S, et al; for the SPARTAN investigators. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018 Apr;378(15):1408-1418.
7. Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018 Jun;378(26):2465-2474.
8. Beaver JA, Kluetz PG, Padzur R. Metastasis-free survival — a new endpoint in prostate cancer trials. N Engl J Med. 2018 Jun;378(26):2458-2460.
9. Hong JH, Kim IY. Nonmetastatic castration-resistant prostate cancer. Korean J Urol. 2014 Mar;55(3):153-160.
10. Penson DF, Armstrong AJ, Concepcion R, et al. Enzalutamide versus bicalutamide in castration-resistant prostate cancer: the STRIVE Trial. J Clin Oncol 2016 Jun 20;34(18):2098-2106.
11. Keating NL, O'malley AJ, Freedland SJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. J Natl Cancer Inst. 2010 Jan 6;102(1):39-46.
12. Iacovelli R, Verri E, Cossu rocca M, et al. The incidence and relative risk of cardiovascular toxicity in patients treated with new hormonal agents for castration-resistant prostate cancer. Eur J Cancer. 2015 Jul 10;51(14):1970-1977.
13. Mateo J, Fizazi K, Gillessen S, et al. Managing nonmetastatic castration-resistant prostate cancer. Eur Urol. 2019 Feb;75(2):285-293.
14. Koo PJ. Imaging controversies for localized and advanced prostate cancer. https://www.urotoday.com/journal/everyday-urology-oncology-insights/articles/107136-imaging-controversiesfor-localized-and-advanced-prostate-cancer.html Accessed February 17, 2019.
15. Whitney CA, Howard LE, Freedland SJ, et al. Impact of age, comorbidity, and PSA doubling time on long-term competing risks for mortality among men with non-metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis. 2018 Oct 2. [Epub ahead of print]
16. Feng FY, Thomas S, Gormley M, et al. Identifying molecular determinants of response to apalutamide (APA) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) in the SPARTAN trial. Poster presented at: American Society for Clinical Oncology Genitourinary Cancers Symposium; February 14, 2019; San Francisco, CA. https://meetinglibrary.asco.org/record/170087/abstract Accessed February 17, 2019.
16. Vicier C, Xie W, Hamid A, et al. Impact of new systemic therapies on outcomes of patients with non-metastatic castration-resistant prostate cancer (nmCRPC). Poster presented at American Society for Clinical Oncology Genitourinary Cancers Symposium; February 14, 2019; San Francisco, CA. https://meetinglibrary.asco.org/record/169887/abstract Accessed February 17, 2019.
17. Saad F, Morlock R, Ivanescu C, et al. Association between urinary, bowel, and hormonal treatment-related symptoms and clinical outcomes in nonmetastatic castration-resistant prostate cancer (nmCRPC): PROSPER study. Poster presented at American Society for Clinical Oncology Genitourinary Cancers Symposium; February 14, 2019; San Francisco, CA. https://meetinglibrary.asco.org/record/169844/abstract Accessed February 17, 2019.
18. Freedland SJ, Ramaswamy K, Lechpammer S, et al. Impact of prostate-specific antigen doubling time on time to metastasis and overall survival in non-metastatic castration-resistant prostate cancer patients. Poster presented at: American Society for Clinical Oncology Genitourinary Cancers Symposium; February 15, 2019; San Francisco, CA. https://meetinglibrary.asco.org/record/169852/abstract Accessed February 17, 2019.at:Freedland SJ, Ramaswamy K, Lechpammer S, et al. Impact of prostate-specific antigen doubling time on time to metastasis and overall survival in non-metastatic castration-resistant prostate cancer patients. Poster presented at: American Society for Clinical Oncology Genitourinary Cancers Symposium; February 15, 2019; San Francisco, CA. https://meetinglibrary.asco.org/record/169852/abstract Accessed February 17, 2019.
19. De Giorgi U, Efsathiou E, Berry WR, et al. A phase III, randomized, double-blind, placebo-controlled study of enzalutamide in men with nonmetastatic castration-resistant prostate cancer: Post-hoc analysis of PROSPER by prior therapy. Poster presented at: American Society for Clinical Oncology Genitourinary Cancers Symposium; February 14, 2019; San Francisco, CA. https://meetinglibrary.asco.org/record/170134/abstract Accessed February 18, 2019.
20. Tombal BF, Armstrong AJ, Barrus JK, et al. Adverse events of special interest assessed by review of safety data in enzalutamide castration-resistant prostate cancer (CRPC) trials. Poster presented at: American Society for Clinical Oncology Genitourinary Cancers Symposium; February 14, 2019; San Francisco, CA. https://meetinglibrary.asco.org/record/170029/abstract Accessed February 18, 2019.
21. Tombal BF, Saad F, Penson D, et al. Patient-reported outcomes following enzalutamide or placebo in men with non-metastatic, castration-resistant prostate cancer (PROSPER): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2019 Feb 12. doi: 10.1016/S1470-2045(18)30898-2 [Epub ahead of print]
22. Anker MS, Lehmann LH, Anker SD. Enzalutamide in castration-resistant prostate cancer. N Engl J Med. 2018 Oct 4;379(14):1380. Comment in: Enzalutamide in Castration-Resistant Prostate Cancer. [N Engl J Med. 2018]
23. Small, Eric J. “ASCO GU 2019: Updated Analysis of Progression-Free Survival with First Subsequent Therapy and Safety in the SPARTAN Study of Apalutamide in Patients with High-Risk Nonmetastatic Castration-Resistant Prostate Cancer.” UroToday, 15 Feb. 2019, www.urotoday.com/conference-highlights/asco-gu-2019/asco-gu-2019-prostate-cancer/110262-asco-gu-2019-updated-analysis-of-progression-free-survival-with-first-subsequent-therapy-and-safety-in-the-spartan-study-of-apalutamide-in-patients-with-high-risk-nonmetastatic-castration-resistant-prostate-cancer.html
Physician-Scientist Review Articles
State of the Evidence Review Articles
Written by Christopher J.D. Wallis, MD, PhD and Zachary Klaassen, MD, MSc
September 17, 2020
While there have been dramatic changes in treatment options for patients with advanced prostate cancer over the past 5 years, perhaps the greatest change has been for patients with non-metastatic castration-resistant prostate cancer (nmCRPC). Prior to February 14, 2018, there were no agents approved by the United States Food and Drug Administration (FDA) for men with nmCRPC.
Written by Jeanny B. Aragon-Ching, M.D., F.A.C.P.
May 15, 2020
Darolutamide is a novel anti-androgen that is recently approved for men with non-metastatic castration-resistant prostate cancer. Darolutamide is structurally different from the previously discovered androgen receptor (AR) agents enzalutamide, bicalutamide and apalutamide. Early phase trials showed promising results with overall safety profiles that are generally well-tolerated.
Written by Zachary Klaassen, MD, MSc and Christopher J.D. Wallis, MD, PhD
April 16, 2019
Over the last two or more years, the treatment of men with M0 CRPC has drastically changed, most recently with the approval of darolutamide in this disease space based on data from the ARAMIS trial. The objective of this article is to provide a contemporary review of treatment options for men with non-metastatic CRPC.
Conference Coverage
Conference Highlights Written by Physician-Scientist
Presented by Evan Yu, MD

At the 2022 ASCO Annual Meeting, the poster session focused on Prostate, Testicular, and Penile cancers included a presentation from Dr. Evan Yu examining real-world outcomes for patients treated with darolutamide in advanced prostate cancer.

 

Presented by Amanda E. Hird, MD,
 In a moderated poster presentation at the 2022 American Urologic Association Annual Meeting held in New Orleans and virtually, Dr. Hird presented results of a population-based analysis of the prevalence and natural history of non-metastatic castration-resistant prostate cancer (nmCRPC).
Presented by Karim Fizazi, MD, PhD
Darolutamide (DARO) is a structurally distinct androgen receptor inhibitor (ARI) that has been demonstrated to significantly prolong metastasis-free survival and overall survival in the ARAMIS trial.1
Presented by Susan Feyerabend
Darolutamide significantly prolonged metastasis-free survival (MFS) and overall survival (OS) vs placebo (PBO) in men with nonmetastatic castration-resistant prostate cancer (nmCRPC) in ARAMIS.
Presented by Karim Fizazi, MD, PhD
Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) need therapy that prolongs survival with little added toxicity, thus preserving quality of life.
Presented by Neal D. Shore, MD, FAC
In plenary abstract presentation in the Poster Highlights Session: Prostate Cancer - Localized Disease session at the 2021 ASCO GU meeting, Dr. Shore and colleagues presented an analysis examining the effect of crossover on the overall survival benefit seen in ARAMIS.
Presented by Maha H. A. Hussain, MD, FACP, FASCO
To provide guidance on expected outcomes and explore the influence of PSA dynamics further, in a plenary abstract presentation in the Poster Highlights Session: Prostate Cancer session at the 2021 ASCO GU Cancers Symposium, Dr. Hussain and colleagues presented an analysis of overall survival and metastasis-free survival among patients in the PROSPER trial according to the depth of PSA response.
Presented by Matthew R. Smith, MD, Ph.D
There has been a rapid evolution in treatment options for patients with non-metastatic castration-resistant prostate cancer (nmCRPC) since the spring of 2018. Up until the presentation of SPARTAN and PROSPER trials, reporting on the use of apalutamide and enzalutamide in nmCRPC
Presented by Alicia Morgans, MD, MPH 
In a stand-alone session at this year’s Society of Urologic Oncology (SUO) virtual annual meeting, titled Understanding the Evolving Treatment Landscape in Prostate Cancer: How to Leverage the Latest Advances and Strategies to Optimize Patient Outcomes,
Presented by Karim Fizazi, MD, Ph.D.
There has been a rapid evolution in treatment options for patients with non-metastatic castration-resistant prostate cancer (nmCRPC) since the spring of 2018. Up until the presentation of SPARTAN and PROSPER trials, reporting on the use of apalutamide and enzalutamide in non-metastatic castration-resistant prostate cancer, at GU ASCO in February 2018, there were no specifically approved treatment options for these patients.
Presented by Karim Fizazi, MD, PhD
There has been a rapid evolution in treatment options for patients with non-metastatic castration-resistant prostate cancer since the spring of 2018. Up until the presentation of SPARTAN and PROSPER trials, reporting on the use of apalutamide and enzalutamide in non-metastatic castration-resistant prostate cancer, at GU ASCO in February 2018, there were no specifically approved treatment options for these patients.
Presented by Karim Fizazi, MD, Ph.D.
Darolutamide is a unique androgen receptor inhibitor, FDA approved in July 2019 for the treatment of non-metastatic castration-resistant prostate cancer. This approval was based on ARAMIS,1 a large multicenter double-blind, placebo-controlled study that randomized 1500 patients to 600 milligrams of darolutamide twice a day or placebo.
Presented by Boris Hadaschik, MD
Athens, Greece (UroToday.com) Dr. Boris Hadaschik presented on the disease entity of non-metastatic castrate-resistant prostate cancer (nmCRPC).
Presented by Matthew R. Smith, MD, PhD
Barcelona, Spain (UroToday.com) The randomized, phase 3 SPARTAN trial showed that apalutamide offered a metastasis-free survival (MFS) benefit over placebo for patients with non-metastatic
Presented by Christopher Parker, MD
Barcelona, Spain (UroToday.com) The optimal timing of radiotherapy after radical prostatectomy for prostate cancer is uncertain. Supporters of adjuvant radiotherapy suggest that earlier treatment may be more effective,
Presented by Matthew R. Smith, MD, PhD
Barcelona, Spain (UroToday.com) In the phase III placebo-controlled SPARTAN study, apalutamide with ongoing androgen deprivation therapy (ADT) significantly improved metastasis-free survival (MFS) (HR 0.28, 95% CI, 0.23-0.35),
Presented by Teuvo Tammela, MD, PhD
Barcelona, Spain (UroToday.com)  Dr. Teuvo Tammela presented results of the recently published ARAMIS trial. Non-metastatic (M0) CRPC (nmCRPC) is defined as a rising PSA in the setting of non-metastatic disease in the castrate state.
Presented by Karim Fizazi, MD, PhD
San Francisco, CA (UroToday.com) The use of androgen-axis targeted agents, specifically enzalutamide and abiraterone, have drastically changed the landscape of advanced prostate cancer management. Just last year, at GU ASCO 2018,
Presented by Neil Fleshner, MD, MPH, FRCSC
Toronto, Ontario (UroToday.com) Dr. Neil Fleshner presented the question in debate of whether we should be treating non-metastatic castrate-resistant prostate cancer (nmCRPC) patients or wait until they have developed metastases.
Presented by Maha Hussain, MD, FACP, FASCO
San Francisco, CA (UroToday.com) Dr. Maha Hussain provided the first presentation of the phase III randomized double-blind controlled trial, the following men were eligible for inclusion
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