Expanding Treatment Options in Non-metastatic Castrate-resistant Prostate Cancer

Prostate cancer (PCa) is the second most common form of cancer diagnosed in US men. It represents 19% of newly diagnosed cancers, and the third leading cause of cancer death, accounting for an estimated 39,430 deaths in 2018.1  Most patients with localized PCa will undergo curative definitive therapy with either surgery or radiotherapy and will be monitored for biochemical recurrence with serial prostate-specific antigen (PSA) serum measurements.2 Approximately a third of treated localized PCa patients will have a recurrence.3 Although survival outcomes for localized PCa approach 100%, the optimal treatment for metastatic PCa is not optimal and still being researched. 

For initial metastatic disease, the current standard of care is hormonal therapy in the form of androgen deprivation therapy (ADT).4 However, patients with hormone-sensitive PCa (HSPC) will still eventually develop a castration-resistant state despite castrate levels of testosterone (less than 50 ng/mL or 1.7 nmol/l). Approximately 10–20% of transitions to the castrate-resistant state will occur in the first five years from initiation of ADT.3 This disease state of castration-resistant prostate cancer (CRPC) is defined as disease progression despite reaching castrate testosterone levels. It can present as either a continuous rise in serum PSA levels, progression of pre-existing disease, and/or the appearance of new metastases.5 The CRPC state can be categorized as either metastatic (mCRPC) or nonmetastatic (nmCRPC).6 Despite improvements in treatment in the last several years, mCRPC remains a lethal disease state with a median survival of fewer than 3 years.6 Although other mechanisms exist, the described “resistance” to castration results from alterations in the androgen receptor (AR) levels, mutations and function, and PCa intracrine androgen synthesis.4, 7

nmCRPC ultimately evolves to mCRPC and the average duration of this transition from ADT initiation is 19 months.nmCRPC is defined by the National Comprehensive Cancer Network (NCCN) as PSA or disease progression occurring despite treatment with primary ADT and in the absence of obvious disease seen in conventional imaging.9, 10 The American Urology Association (AUA) defines the nmCRPC patient as Index Patient number one,11 and a more elaborate definition is provided by the Prostate Cancer Working Group (PCWG)3 which includes: a minimum PSA level of 1.0 ng/mL, a rising PSA that is at least 2 ng/mL higher than the nadir PSA, castrate levels of testosterone, and no radiographic evidence of metastases.12

There are approximately 100,000 nmCRPC patients in the US, with an annual estimated incidence of 50,000–60,000. Approximately 34% of these patients are expected to progress to mCRPC every year, with nearly 60% progressing within 5 years.10 In Europe, the prevalence of nmCRPC has been estimated to be 7% of all PCa patients.13 PSA levels and PSA doubling time (PSADT) can be used to measure nmCRPC disease aggressiveness. A PSA above 8 ng/ml or PSADT less than 10 months is regarded as high-risk markers for rapid progression, with ADT being recommended earlier rather than later in these patients.14 PSA and testosterone monitoring during ADT should occur every 3–6 months for those with low risk disease (PSA<8 ng/ml and PSADT>10 months) and/or good prior response to ADT, to more intensive schedules for those with a high-risk disease (PSA>8 ng/ml and PSADT<=10 months).15 Without any treatment, the median bone metastasis-free survival (MFS) in nmCRPC ranges between 25–30 months, with up to 70% of patients remaining bone-metastases-free after two years.16 Once disease progression occurs, it can worsen urinary symptoms and sexual function, restrict activity and have an emotional impact.17

Imaging modalities recommended for initial assessment of disease progression include 99mTc bone scintigraphy and computed tomography of the abdomen, pelvis, and chest. Other imaging modalities that could be considered include MRI, and 18F-sodium fluoride positron emission tomography (NaF PET). Imaging should be performed when the PSA levels are higher than 2 ng/mL,12 and reimaging should be performed when PSA levels are higher than 5 ng/ml and later on when PSA level doubles.16 In nmCRPC micro-metastases might exist but are usually undetectable by conventional imaging techniques.18 In the near future, new imaging techniques (Choline-, Fluciclovine-, PSMA-PET scan) will most likely change the landscape of this disease. With the growing use of more sensitive imaging modalities, such as the PSMA-PET, NaF PET, and 11C-choline PET/CT, the nmCRPC space will continue to evolve enabling earlier and more accurate diagnosis of measurable metastatic disease.19-22

Treatment for non-metastatic castrate resistant prostate cancer

In the past, treatment for nmCRPC included observation, measuring PSADT with serial imaging until metastasis was seen. Due to the lack of guidelines and consensus in this unique disease space, patients were encouraged to enroll in clinical trials. Recently, a growing interest in the treatment of nmCRPC has been seen in an attempt to delay progression to mCRPC. The ultimate goal was and continues to be that novel androgen-modulating drugs could potentially delay the transition from nmCRPC to mCRPC, prolong progression-free survival (PFS) and eventually, overall survival (OS).

First-generation anti-androgens and hormonal manipulation

Continuing ADT was the most commonly used strategy for nmCRPC patients. A 2 to 6-month median survival advantage was reported in nmCRPC patients who were castrated compared to those discontinuing ADT once CRPC developed.23 There is data supporting that the AR may independently be oncogenic, despite maximum blockade, and should remain a target, using ADT, for modifying disease progression.24 Human autopsy studies have also shown varying heterogeneity within PCa cells with variable response to androgens,25 adding to the logic behind the continuation of ADT in these patients. There is also an option of adding a first-generation antiandrogen (bicalutamide, nilutamide, and flutamide) to an existing ADT regimen, but this has shown a limited survival benefit in only a third of patients, with an increased rate of adverse effects.26 Interestingly, antiandrogen withdrawal can also result in a temporary PSA level decrease in a third of patients who were treated with maximum androgen blockade. There is also data showing that long-term use of antiandrogens can lead to AR modulation, converting antiandrogens to AR agonists.17 Importantly, there is currently no data to support changing ADT with different GnRH analogues,27 or GnRH antagonists.3, 28

Second generation anti-androgens

The three FDA-approved second-generation anti-androgens include enzalutamide, apalutamide, and darolutamide.  These second-generation antiandrogens harbor several advantages over the first-generation ones, including a higher affinity for the AR, lack of agonistic properties, and an ability to inhibit AR function through three distinct mechanisms:  a) Prevention of androgen binding to the AR, b) Prevention of AR translocation to the nucleus, and c) Prevention of the AR binding to DNA.29 Until February 2018, there were no FDA-approved treatments for nmCRPC, and prior to the landmark clinical trials introducing enzalutamide (PROSPER trial),30 apalutamide (SPARTAN trial)14 and darolutamide (ARAMIS trial)31 nmCRPC patients continued to receive ADT alone.


Apalutamide binds to the same ligand binding site as bicalutamide but has a 7- to 10-fold higher affinity for the AR.32 Apalutamide has a similar mechanism of action to enzalutamide but has been shown to have greater anti-tumor activity than enzalutamide in a murine model.33 The SPARTAN was a prospective double-blind multicenter phase III randomized trial involving 1207 nmCRPC patients and comparing apalutamide with placebo in a 2:1 fashion14 (Figure 1). At the time of study inclusion, the authors utilized conventional imaging scans to detect metastases with computed tomography (CT) scans of the chest, abdomen, pelvis, and head as well as technetium scintigraphy bone scans. Routine re-staging scans were performed every 16 weeks. The primary endpoint was MFS, which was significantly better in apalutamide-treated patients (40.5 vs. 16.2 months, HR: 0.28, 95% CI: 0.23-0.35; P < 0.001).14 This represents a 72% reduction in the risk of distant metastasis or death with apalutamide. All secondary endpoints were also significantly improved with apalutamide.14 Symptomatic progression was also significantly improved in those who received apalutamide (HR of 0.45, 95% CI: 0.32-0.63, and P < 0.001).14 After a median follow-up of 20.3 months, initial survival analysis showed an HR of 0.7 (95% CI: 0.47-1.04, P = 0.07) favoring apalutamide, although longer follow-up is needed to confirm the OS benefit. For apalutamide several adverse events were more common (23.8% vs. 5.5%), including hypothyroidism (8.1% vs 2%), and fractures (11.7% vs 6.5%). Only two cases of seizures occurred in the apalutamide arm, and there was no increase in the risk of serious adverse events (24.8% vs 23.1%). A higher risk of death was apparent in apalutamide-treated patients (ten patients in the apalutamide arm vs. one patient in the placebo arm).14 Based on the results of the SPARTAN trial, apalutamide received FDA approval for the management of nmCRPC in February 2018.

figure 1 SPARTAN trial

Figure 1
. SPARTAN trial design


Enzalutamide is another second-generation AR antagonist which has been previously evaluated and established as a treatment for mCRPC,34, 35 receiving FDA approval in 2012. The PROSPER trial was a phase III, double-blinded, prospective randomized study evaluating 1401 nmCRPC patients randomized 2:1 to enzalutamide vs placebo30 (Figure 2). The primary endpoint was MFS, and secondary endpoints included time to PSA progression, time to first use of new antineoplastic therapy, OS and safety. Enzalutamide significantly prolonged median MFS (36.6 months vs 14.7 months [p < 0.0001]), time to first use of new antineoplastic therapy (39.6 months vs 17.7 months [p < 0.0001]), and time to PSA progression (37.2 months vs 3.9 months [p <0.0001]) compared with placebo.30 Initial analysis of OS showed that there was a trend in favor of enzalutamide (HR = 0.80; p = 0.1519). The median duration of treatment was 18.4 months compared with 11.1 months for enzalutamide and placebo, respectively. Adverse events were higher with enzalutamide vs placebo (any grade adverse effects: 87% vs 77%; grade⩾3 adverse effects: 31% vs 23%; serious adverse effects: 24% vs 18%).30 Adverse events led to death in 3% of enzalutamide treated patients vs. 1% in the placebo arm. Cardiac events leading to death occurred in 9 patients (1%) receiving enzalutamide and 2 patients (<1%) receiving placebo. Based on the results of the PROSPER trial, enzalutamide was FDA-approved in July 2018 for nmCRPC patients with PSADT of 10 months.

figure 2 PROSPER trial

Figure 2. PROSPER trial design

Both SPARTAN and PROSPER trials utilized MFS as a primary endpoint. This allows for more expeditious completion of trials and investigations of therapies. While a long follow-up time leading to OS is still the ultimate endpoint, MFS has been shown as a predictor for men with biochemically recurrent PCa. More recently, the ICECaP working group had also established MFS as a strong surrogate for OS in localized cancer.27, 36


Darolutamide, formerly known as ODM-201, is a novel androgen-targeted signaling inhibitor. Pre-clinical studies showed that darolutamide inhibits the AR more potently than other second-generation anti-androgens such as enzalutamide and apalutamide by increased anti-tumor activity. Darolutamide is also unique due to its ability to inhibit mutant ARs.37 Darolutamide also has a negligible ability to cross the blood-brain barrier, conferring lower risk for seizures compared to enzalutamide and apalutamide.

The ARAMIS trial is a prospective randomized double-blind placebo-controlled phase III, multicenter trial. It evaluated the safety and efficacy of darolutamide in 1502 nmCRPC patients who were at a high risk of developing metastatic disease (defined as PSADT<10 months, and PSA > 2ng/dl).31 Patients were randomized 2:1 to receive either darolutamide twice daily or placebo while continuing ADT (Figure 3). Patients were stratified by PSADT (≤6 months or >6 months) and use of osteoclast-targeted therapy. Included men were those with PSA ≥ 2 ng/mL, ECOG 0-1, and PSADT ≤ 10 months. The primary endpoint of this study was MFS, defined as the time between randomization and evidence of metastasis or death from any cause.31 The secondary objectives included OS, time to first symptomatic skeletal event (SSE), time to initiation of first cytotoxic chemotherapy, time to pain progression, and characterization of the safety and tolerability of darolutamide. The results showed that the median MFS was 40.4 months with darolutamide vs 18.4 months with placebo (HR 0.41, 95%CI 0.34–0.50), representing a 59% reduction in metastases or death among patients receiving darolutamide.31 OS also favored darolutamide (median not reached for both arms, HR 0.71, 95%CI 0.50–0.99, two-sided p=0.045), as did time to pain progression (HR 0.65, 95% CI 0.53–0.79; two-sided p<0.0001. However, the OS data had still not completely matured. Other secondary and exploratory efficacy endpoints also favored darolutamide over placebo, including PFS: 62% reduced risk of local progression, distant metastases or death (36.8 months vs. 14.8 months, HR 0.38, p < 0.0001); time to first cytotoxic chemotherapy: HR 0.43, p < 0.001; time to SSE: HR 0.43, p = 0.011. The rate of grade 3-5 adverse events was similar between the two groups with 24.7% in the darolutamide arm vs. 19.5% in the placebo arm.31 Based on the results of the ARAMIS trial, darolutamide was FDA-approved on July 30, 2019, for the use in nmCRPC patients.

figure 3 ARAMIS trial

Figure 3. ARAMIS trial design

Table 1 summarizes and compares the three FDA-approved second-generation antiandrogens for the treatment of nmCRPC patients.

Table 1. Comparison of the second-generation androgen receptor antagonists for nmCRPC

table 1 comparison of the second generation androgen receptor antagonists for nmCRPC

HR = Hazard ratio, MFS = Metastases free survival, Mo = Months, NA = Not available, nmCRPC = Non-metastatic castrate resistant prostate cancer, OS = Overall survival, PFS = Progression free survival, PSA = Prostate specific antigen, PSADT = PSA doubling time

Bone-targeted therapy

Bone metastasis is commonly the first site of PCa metastasis. Therefore, bone-targeted agents (clodronate, zoledronic acid, and denosumab) have been investigated for use in nmCRPC but have not shown any improvement in OS. There are therefore not FDA approved for nmCRPC patients.38 Other two potent bone-targeted agents (endothelin-A receptor antagonists, atrasentan and zibotentan) were also studied to determine their efficacy in preventing bony metastases in nmCRPC patients. However, both studies failed to show an OS benefit in these agents.39, 40


Sipuleucel-T, an immunotherapeutic agent designed to elicit a T-cell-mediated response against prostatic acid phosphatase antigen in PCa cells, has been previously investigated in a study including nmCRPC patients. This study had a limited sample size and sipuleucel-T demonstrated a tendency to increase PSADT, thus its role was no longer pursued in this disease space.41 Use of poxvirus-based PSA vaccine (PSA-TRICOM) with nilutamide in patients with nmCRPC has been shown to improve median survival in a study with a very small sample size.42 Lastly, Bevacizumab (Avastin), a humanized monoclonal antibody against vascular endothelial growth factor A (VEGF-A), was also analyzed as a possible treatment option for nmCRPC patients. However, this treatment was shown to have a minimal impact on the disease course.43


Abiraterone acetate is an irreversible CYP17 inhibitor targeting androgen biosynthesis in the testicles, adrenal glands, and within the PCa tumor cells. The IMAAGEN trial was a phase II, multicenter study that evaluated PSA responses to abiraterone acetate in 131 nmCRPC patients with a PSA higher than 10 ng/mL or a PSADT lower than 10 months.44 The primary endpoint of the study was PSA response at 6 months. The results demonstrated that 87% of patients exhibited a PSA decline of more than 50% and 60% of the patients had a PSA decline of over 90% at 6 months.44 The median time to PSA progression and to radiographic progression was 28.7 months and not reached, respectively.44 The toxicity profile of abiraterone was similar to that reported in phase III trials assessing its role in mCRPC patients.44 To our knowledge there are currently no ongoing phase III trials assessing the role of abiraterone in nmCRPC.

Orteronel (TAK-700)

A phase II study investigated orteronel (TAK-700) a nonsteroidal oral inhibitor of androgen synthesis (17,20-lyase inhibitor) in the nmCRPC setting (NCT01046916).45 The primary endpoint was the proportion of patients achieving a PSA less than 0.2 ng/dL at 3 months. The trial showed that a PSA decrease of more than 30% was observed 90% of patients, and 16% of patients achieved a PSA lower than 0.2 ng/dl after three months.45 PSA progression rate was 57% at 12 months and 42% at 24 months, while MFS rate was 94% and 62% at 12 and 24 months, respectively.45 However, this drug’s development was stopped in 2014, as no OS improvement was reported in a phase III study with mCRPC patients (NCT01193257, ELMPC5).46

Sequencing novel treatments in non-metastatic castrate resistant prostate cancer space

Similar to the dilemma faced in mCRPC, it is currently unclear which agent to use first in nmCRPC patients. The final decision should incorporate various factors including adverse effects, drug availability, patient preferences, and cost issues. The future use of more sensitive imaging that may detect micrometastatic disease earlier, could potentially impact the decision which agent to use first. Additionally, it is not clear if the improved MFS reported in all three trials assessing the second-generation antiandrogens, will ultimately translate to improved OS, once all the trials have matured.32 Lastly, it is also important to monitor the ongoing effects of these medications on patients, including frailty, fractures, and central nervous system effects, which may not be so trivial following an extended treatment duration.32


In the last 18 months, we have witnessed significant additions to the treatment armamentarium of nmCRPC. There is no doubt that additional discoveries in the near future would even further change the current treatment landscape of nmCRPC. These include the standardization of novel and more specific imaging modalities, the study of different treatment combinations, and deciphering the correct sequence of treatments.

Published Date: January 22nd, 2020
Written by: Hanan Goldberg MD, Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA
  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. Jan 2018;68(1):7-30.
  2. Trapasso JG, deKernion JB, Smith RB, Dorey F. The incidence and significance of detectable levels of serum prostate specific antigen after radical prostatectomy. J Urol. Nov 1994;152(5 Pt 2):1821-1825.
  3. Tombal B, Miller K, Boccon-Gibod L, et al. Additional analysis of the secondary end point of biochemical recurrence rate in a phase 3 trial (CS21) comparing degarelix 80 mg versus leuprolide in prostate cancer patients segmented by baseline characteristics. Eur Urol. May 2010;57(5):836-842.
  4. Karantanos T, Evans CP, Tombal B, Thompson TC, Montironi R, Isaacs WB. Understanding the mechanisms of androgen deprivation resistance in prostate cancer at the molecular level. Eur Urol. Mar 2015;67(3):470-479.
  5. Saad F, Hotte SJ. Guidelines for the management of castrate-resistant prostate cancer. Canadian Urological Association journal = Journal de l'Association des urologues du Canada. 2010;4(6):380-384.
  6. Alpajaro SIR, Harris JAK, Evans CP. Non-metastatic castration resistant prostate cancer: a review of current and emerging medical therapies. Prostate Cancer Prostatic Dis. Mar 2019;22(1):16-23.
  7. Chandrasekar T, Yang JC, Gao AC, Evans CP. Mechanisms of resistance in castration-resistant prostate cancer (CRPC). Transl Androl Urol. Jun 2015;4(3):365-380.
  8. Sharifi N, Dahut WL, Steinberg SM, et al. A retrospective study of the time to clinical endpoints for advanced prostate cancer. BJU Int. Nov 2005;96(7):985-989.
  9. Macomson B, Lin JH, Tunceli O, et al. Time to metastasis or death in non-metastatic castrate resistant prostate cancer (nmCRPC) patients by National Comprehensive Cancer Network (NCCN) risk groups. Journal of Clinical Oncology. 2017;35(15_suppl):5027-5027.
  10. Scher HI, Solo K, Valant J, Todd MB, Mehra M. Prevalence of Prostate Cancer Clinical States and Mortality in the United States: Estimates Using a Dynamic Progression Model. PLoS One. 2015;10(10):e0139440.
  11. Lowrance WT, Murad MH, Oh WK, Jarrard DF, Resnick MJ, Cookson MS. Castration-Resistant Prostate Cancer: AUA Guideline Amendment 2018. J Urol. Dec 2018;200(6):1264-1272.
  12. Scher HI, Morris MJ, Stadler WM, et al. Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. Apr 20 2016;34(12):1402-1418.
  13. Liede A, Arellano J, Hechmati G, Bennett B, Wong S. International prevalence of nonmetastatic (M0) castration-resistant prostate cancer (CRPC). Journal of Clinical Oncology. 2013;31(15_suppl):e16052-e16052.
  14. Smith MR, Saad F, Chowdhury S, et al. Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. New England Journal of Medicine. 2018;378(15):1408-1418.
  15. Virgo KS, Rumble RB, Singer EA. Second-Line Hormonal Therapy for Men With Chemotherapy-Naive Castration-Resistant Prostate Cancer: American Society of Clinical Oncology Provisional Clinical Opinion Summary. J Oncol Pract. Jul 2017;13(7):459-461.
  16. Crawford ED, Stone NN, Yu EY, et al. Challenges and recommendations for early identification of metastatic disease in prostate cancer. Urology. Mar 2014;83(3):664-669.
  17. Sartor AO, Tangen CM, Hussain MH, et al. Antiandrogen withdrawal in castrate-refractory prostate cancer: a Southwest Oncology Group trial (SWOG 9426). Cancer. Jun 2008;112(11):2393-2400.
  18. Murray NP, Reyes E, Tapia P, Badínez L, Orellana N. Differential expression of matrix metalloproteinase-2 expression in disseminated tumor cells and micrometastasis in bone marrow of patients with nonmetastatic and metastatic prostate cancer: theoretical considerations and clinical implications-an immunocytochemical study. Bone marrow research. 2012;2012:259351-259351.
  19. Eiber M, Maurer T, Souvatzoglou M, et al. Evaluation of Hybrid (6)(8)Ga-PSMA Ligand PET/CT in 248 Patients with Biochemical Recurrence After Radical Prostatectomy. J Nucl Med. May 2015;56(5):668-674.
  20. Morigi JJ, Stricker PD, van Leeuwen PJ, et al. Prospective Comparison of 18F-Fluoromethylcholine Versus 68Ga-PSMA PET/CT in Prostate Cancer Patients Who Have Rising PSA After Curative Treatment and Are Being Considered for Targeted Therapy. J Nucl Med. Aug 2015;56(8):1185-1190.
  21. Umbehr MH, Muntener M, Hany T, Sulser T, Bachmann LM. The role of 11C-choline and 18F-fluorocholine positron emission tomography (PET) and PET/CT in prostate cancer: a systematic review and meta-analysis. Eur Urol. Jul 2013;64(1):106-117.
  22. Geynisman DM, Plimack ER, Zibelman M. Second-generation Androgen Receptor-targeted Therapies in Nonmetastatic Castration-resistant Prostate Cancer: Effective Early Intervention or Intervening Too Early? Eur Urol. Dec 2016;70(6):971-973.
  23. Taylor CD, Elson P, Trump DL. Importance of continued testicular suppression in hormone-refractory prostate cancer. J Clin Oncol. Nov 1993;11(11):2167-2172.
  24. Scher HI, Sawyers CL. Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol. Nov 10 2005;23(32):8253-8261.
  25. Shah RB, Mehra R, Chinnaiyan AM, et al. Androgen-independent prostate cancer is a heterogeneous group of diseases: lessons from a rapid autopsy program. Cancer Res. Dec 15 2004;64(24):9209-9216.
  26. Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Prostate Cancer Trialists' Collaborative Group. Lancet. Apr 29 2000;355(9214):1491-1498.
  27. Schweizer MT, Zhou XC, Wang H, et al. Metastasis-free survival is associated with overall survival in men with PSA-recurrent prostate cancer treated with deferred androgen deprivation therapy. Ann Oncol. Nov 2013;24(11):2881-2886.
  28. Schroder FH, Tombal B, Miller K, et al. Changes in alkaline phosphatase levels in patients with prostate cancer receiving degarelix or leuprolide: results from a 12-month, comparative, phase III study. BJU Int. Jul 2010;106(2):182-187.
  29. Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. May 8 2009;324(5928):787-790.
  30. Hussain M, Fizazi K, Saad F, et al. Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer. New England Journal of Medicine. 2018;378(26):2465-2474.
  31. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. New England Journal of Medicine. 2019;380(13):1235-1246.
  32. El-Amm J, Aragon-Ching JB. The Current Landscape of Treatment in Non-Metastatic Castration-Resistant Prostate Cancer. 2019;13:1179554919833927.
  33. Clegg NJ, Wongvipat J, Joseph JD, et al. ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res. Mar 15 2012;72(6):1494-1503.
  34. Scher HI, Fizazi K, Saad F, et al. Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy. New England Journal of Medicine. 2012;367(13):1187-1197.
  35. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. Jul 31 2014;371(5):424-433.
  36. Xie W, Regan MM, Buyse M, et al. Metastasis-Free Survival Is a Strong Surrogate of Overall Survival in Localized Prostate Cancer. J Clin Oncol. Sep 20 2017;35(27):3097-3104.
  37. Shore ND. Darolutamide (ODM-201) for the treatment of prostate cancer. Expert Opin Pharmacother. Jun 2017;18(9):945-952.
  38. Smith MR, Saad F, Oudard S, 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. Oct 20 2013;31(30):3800-3806.
  39. Nelson JB, Love W, Chin JL, et al. Phase 3, randomized, controlled trial of atrasentan in patients with nonmetastatic, hormone-refractory prostate cancer. Cancer. Nov 1 2008;113(9):2478-2487.
  40. Miller K, Moul JW, Gleave M, et al. Phase III, randomized, placebo-controlled study of once-daily oral zibotentan (ZD4054) in patients with non-metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis. Jun 2013;16(2):187-192.
  41. Beinart G, Rini BI, Weinberg V, Small EJ. Antigen-presenting cells 8015 (Provenge) in patients with androgen-dependent, biochemically relapsed prostate cancer. Clin Prostate Cancer. Jun 2005;4(1):55-60.
  42. Madan RA, Gulley JL, Schlom J, et al. Analysis of overall survival in patients with nonmetastatic castration-resistant prostate cancer treated with vaccine, nilutamide, and combination therapy. Clin Cancer Res. Jul 15 2008;14(14):4526-4531.
  43. Ogita S, Tejwani S, Heilbrun L, et al. Pilot Phase II Trial of Bevacizumab Monotherapy in Nonmetastatic Castrate-Resistant Prostate Cancer. ISRN oncology. 2012;2012:242850-242850.
  44. Ryan CJ, Crawford ED, Shore ND, et al. The IMAAGEN Study: Effect of Abiraterone Acetate and Prednisone on Prostate Specific Antigen and Radiographic Disease Progression in Patients with Nonmetastatic Castration Resistant Prostate Cancer. J Urol. Aug 2018;200(2):344-352.
  45. Hussain M, Corn PG, Michaelson MD, et al. Phase II study of single-agent orteronel (TAK-700) in patients with nonmetastatic castration-resistant prostate cancer and rising prostate-specific antigen. Clin Cancer Res. Aug 15 2014;20(16):4218-4227.
  46. Fizazi K, Jones R, Oudard S, et al. Phase III, randomized, double-blind, multicenter trial comparing orteronel (TAK-700) plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or after docetaxel-based therapy: ELM-PC 5. J Clin Oncol. Mar 1 2015;33(7):723-731.