Novel Androgen Receptor Signaling Inhibitors for Nonmetastatic Castration-Resistant Prostate Cancer: The Light at the End of the Tunnel-or an Oncoming Train?

April 15, 2016

Men with high-risk nonmetastatic CRPC should if possible be enrolled in a clinical trial and that patients with low-risk disease can be safely observed.

For both the patient and provider, managing nonmetastatic castration-resistant prostate cancer (CRPC) can be frustrating. Often, as Luo et al review in this issue of ONCOLOGY,[1] management of nonmetastatic CRPC involves either a waiting game or treatment with agents that have modest activity with acceptable tolerability (eg, first-generation antiandrogens). However, hope is on the horizon in the form of novel androgen receptor signaling inhibitors (ARSIs). Both abiraterone, a CYP17A1 inhibitor able to suppress intratumoral androgens, and enzalutamide, an antagonist of androgen receptor ligand binding, have been tested and approved in increasingly earlier prostate cancer disease states.[2-5] So it is no surprise that enzalutamide, as well as the next-generation antiandrogens ARN-509 and ODM-201, are currently in phase III testing in nonmetastatic CRPC (in the PROSPER, SPARTAN, and ARAMIS trials, respectively).[6-10] Although these trials of ARSIs seem likely to generate the level 1 evidence now sorely lacking, several key issues deserve discussion. Here we will address these issues and provide insights.

Efficacy Endpoints (Benefits)

The primary endpoint in all three ongoing phase III studies in nonmetastatic CRPC is metastasis-free survival. This endpoint is typically a composite defined as time to first occurrence of bone metastasis (whether symptomatic or asymptomatic) or death from any cause. As detailed by Luo and colleagues, metastasis-free survival has previously been evaluated as a primary endpoint in nonmetastatic CRPC.[11] Several lessons can be learned from this earlier phase III, double-blind trial, in which 1,432 men with nonmetastatic CRPC at high risk for metastasis (prostate-specific antigen [PSA] level ≥ 8 ng/mL or PSA doubling time ≤ 10 months, or both) were randomly assigned 1:1 to either the osteoclast inhibitor denosumab or placebo. Denosumab modestly prolonged metastasis-free survival by 4.2 months (hazard ratio [HR], 0.85 [95% CI, 0.73–0.98]; P = .028) but not overall survival (HR, 1.01 [95% CI, 0.85–1.20]; P = .91). Importantly, there was a 5% rate of osteonecrosis of the jaw (ONJ) in the denosumab arm, compared with 0% in the placebo arm. The Oncologic Drugs Advisory Committee of the US Food and Drug Administration (FDA) voted 12 to 1 that the risk-benefit ratio was insufficient to expand use of denosumab to include the indication of delaying spread to the bone in men with high-risk nonmetastatic CRPC, and the FDA did not grant approval.

Thus, it seems that ARSIs must do better than denosumab in terms of risk-benefit ratio. Specifically, in order to have a high likelihood of approval, we believe that novel ARSIs must demonstrate an overall survival advantage, ideally in addition to other patient-centered benefits (ie, increases in time to symptomatic progression, time to first skeletal-related event, and time to initiation of cytotoxic chemotherapy). Furthermore, in a perfect world, any survival difference would be large, because otherwise the question of early vs late use of ARSIs would arise. For example, docetaxel for 6 cycles demonstrated a 13.6-month improvement in overall survival when used in an earlier disease state, compared with a 2.9-month improvement with later use for 10 cycles, essentially resolving this potential debate before it started.[12,13] Finally, ARSIs must be tolerable and not cause clinically meaningful declines in quality of life.

Patient-Reported Outcomes and Quality of Life (Risks)

If ARSIs have clinically significant side effects (like ONJ with denosumab) or are chronically intolerable for the long durations during which they are likely to be used, this also may adversely tilt the risk-benefit ratio. In these men with a median life expectancy of 3 to 4 years, depending on the magnitude of benefits, negative effects on quality of life could prove pivotal to the early-vs-late-use calculus. Of course, the best evidence will come from the large randomized trials (1,200 to 1,560 patients) mentioned previously, but data from two earlier-phase trials is instructive.

The single-arm phase II IMAAGEN trial enrolled 131 patients with high-risk nonmetastatic CRPC and treated them with abiraterone/prednisone. Adverse events (AEs) of grade 3 or higher occurred in 54.9% of patients, and 38.2% had a serious AE, with 13% of patients having an AE resulting in discontinuation of the study drug, and with four patients experiencing AEs that resulted in death.[14] The best available evidence regarding tolerability is from the recently published double-blind, randomized phase II STRIVE trial of enzalutamide vs bicalutamide, which included 139 patients with high-risk nonmetastatic CRPC.[15] (It should be noted that AEs were not reported separately for the nonmetastatic CRPC group.) In the entire study cohort, AEs more commonly reported with enzalutamide than with bicalutamide included fatigue (38% vs 28%), hot flashes (16% vs 10%), falls (14% vs 8%), hypertension (12% vs 5%), dizziness (12% vs 7%), and decreased appetite (12% vs 7%). Interestingly, with a median time on treatment of 8.4 months for bicalutamide vs 14.7 months for enzalutamide, the median time to clinically significant decline of the FACT-P (Functional Assessment of Cancer Therapy-Prostate, a quality-of-life instrument) score appeared equivalent at 8.3 and 8.4 months, respectively. This suggests that while the decline in quality of life with bicalutamide may have been due to disease progression, the decline with enzalutamide was most likely related to treatment effect.

Measures of quality of life included as secondary endpoints in all three phase III studies will be critical. Because patients may report symptoms and health status better than clinicians, future studies of ARSIs should also include tools such as the PRO-CTCAE (Patient-Reported Outcomes version of the National Institutes of Health’s Common Terminology Criteria for Adverse Events).[16] Finally, it is well established that supervised exercise can mitigate a variety of treatment-related adverse effects resulting from conventional androgen deprivation therapy.[17] A study is underway examining whether exercise can mitigate adverse effects of higher-potency ARSIs.[18,19] If exercise can mitigate important side effects of ARSIs, this would likely tilt the risk-benefit balance toward use in a larger number of men.


We wholeheartedly agree with Luo and coauthors that at this time, men with high-risk nonmetastatic CRPC should if possible be enrolled in a clinical trial and that patients with low-risk disease can be safely observed. Phase III studies scheduled to report in about 4 years will shed light on the risk-benefit ratio of second-generation ARSIs. In the meantime, we caution against using these agents off-label for nonmetastatic CRPC due to their significant side effects and the resulting diminishment in quality of life, with uncertain significance of benefits. The Table speculates-pending data from phase III and other trials-how risk stratification for nonmetastatic CRPC treatment selection may look in the not-so-distant future.

Financial Disclosure:Dr. Harrison has received research funding from Janssen and Medivation/Astellas. Dr. Ramalingam has no significant financial interest or other relationship with the manufacturer of any product or provider of any service mentioned in this commentary.


1. Luo J, Beer TM, Graff JN. Treatment of nonmetastatic castration-resistant prostate cancer. Oncology (Williston Park). 2016;30:336-44.

2. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995-2005.

3. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368:138-48.

4. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-97.

5. Beer TM, Armstrong AJ, Sternberg CN, et al. Enzalutamide in men with chemotherapy-naive metastatic prostate cancer (mCRPC): results of phase III PREVAIL study. J Clin Oncol. 2014;32(suppl):abstr LBA1.

6. Medivation. Safety and efficacy study of enzalutamide in patients with nonmetastatic castration-resistant prostate cancer (PROSPER). Accessed February 7, 2016.

7. Aragon. A study of ARN-509 in men with non-metastatic castration-resistant prostate cancer (SPARTAN). Accessed February 7, 2016.

8. Bayer. Efficacy and safety study of BAY1841788 (ODM-201) in men with high-risk non-metastatic castration-resistant prostate cancer (ARAMIS). Accessed February 7, 2016.

9. Moilanen AM, Riikonen R, Oksala R, et al. Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies. Sci Rep. 2015;5:12007.

10. Rathkopf DE, Morris MJ, Fox JJ, et al. Phase I study of ARN-509, a novel antiandrogen, in the treatment of castration-resistant prostate cancer. J Clin Oncol. 2013;31:3525-30.

11. Smith MR, Saad F, Coleman R, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet. 2012;379:39-46.

12. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373:737-46.

13. Berthold DR, Pond GR, Soban F, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol. 2008;26:242-5.

14. Ryan CJ, Crawford ED, Shore ND, et al. Effect of abiraterone acetate and low dose prednisone on prostate-specific antigen in patients with non-metastatic castration-resistant prostate cancer: the results from impact of abiraterone acetate in prostate-specific antigen core study. Presented at the American Urological Association Annual Meeting; May 15-19, 2015; New Orleans, LA.

15. Penson DF, Armstrong AJ, Concepcion R, et al. Enzalutamide versus bicalutamide in castration-resistant prostate cancer: the STRIVE trial. J Clin Oncol. 2016 Jan 25. [Epub ahead of print]

16. Basch E, Reeve BB, Mitchell SA, et al. Development of the National Cancer Institute’s Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). J Natl Cancer Inst. 2014;106.

17. Gardner JR, Livingston PM, Fraser SF. Effects of exercise on treatment-related adverse effects for patients with prostate cancer receiving androgen-deprivation therapy: a systematic review. J Clin Oncol. 2014;32:335-46.

18. Duke. EXTEND exercise trial. Accessed February 8, 2016.

19. Harrison MR, Jones LW. Exercise as treatment for androgen deprivation therapy-associated physical dysfunction: ready for prime time? Eur Urol. 2014;65:873-4.