Non-metastatic castration-resistant prostate cancer, a disease state misnomer that is a seriously unmet therapeutic need

Non-metastatic (M0) castration-resistant prostate cancer (CRPC) is truly a misnomer.  It is meant to highlight a prostate cancer disease state that solely exists because of the use of prostate-specific antigen (PSA).  In most fields, patients either have localized disease or radiographically-detectable metastatic disease.  Since PSA is a highly sensitive measure of detection, our field is able to detect microscopic metastases due to limits of standard imaging modalities. 

This has created a new disease state of men on androgen deprivation therapy who experience castration-resistance with a rising PSA while serum testosterone levels are castrate.  Yet, the therapeutic agents known to prolong survival for CRPC patients were all developed in the radiographically-detected metastatic state.  As a result, this non-metastatic CRPC state has no regulatory approved options proven to prolong survival.  However, this is not for lack of trying, as various therapeutic agents have been unsuccessful in attempts to gain regulatory approval for this misnomer of a disease state.  

There have been 4 large randomized control trials completed in this disease state.  The endothelin receptor antagonists, Atrasentan1 and Zibotentan,2 and a bisphosphonate, zoledronic acid,3 have all been tested against placebo and with no discernible benefit.  However, denosumab, a rank ligand inhibitor, showed for a high-risk population, that bone metastasis free survival was improved compared to placebo.4 Yet it was felt that the level of benefit was not clinically significant enough to warrant regulatory approval.  As a result, various randomized control phase 3 trials are currently ongoing in this disease state with newer agents.

A logical step to take in the field is to take low toxicity, high efficacy agents from standard use in metastatic CRPC and import them for testing in earlier disease states.  Therefore, it is not surprising that enzalutamide, a pure androgen receptor (AR) antagonist, regulatory approved for metastatic CRPC, is currently being tested vs. placebo in the PROSPER randomized, phase 3 trial for non-metastatic CRPC (see link below).  Another pure AR antagonist, apalutamide, which may have less penetration across the blood brain barrier,5 is also being tested in this setting in a trial known as SPARTAN; full accrual was recently completed and we await mature results.  Finally, darolutamide (ODM-201), which has activity as an AR antagonist, with the unique property of inhibiting some known AR mutants,6 is also currently being tested in the ARAMIS randomized phase 3 trial.  All of these trials are similar in that they are enrolling patients with short PSA doubling times, to enrich for a higher risk population for development of radiographically-detectable metastasis.  It is generally felt that the primary endpoint of metastasis-free survival is likely to be satisfactory for regulatory approval for patients in this non-metastatic CRPC patient population if a median improvement of 6 months or more with a favorable safety profile is demonstrated.

The time is now to enroll patients to these large trials, as there is an excellent chance for these agents to have positive results, given the track record of enzalutamide in metastatic CRPC.7,8  This would change the standard of care for non-metastatic CRPC and offer our patients options beyond older agents like bicalutamide, flutamide, nilutamide, ketoconazole and estrogenic agents that are often used in this setting.  Unfortunately, none of these older agents have definitive proven benefit.  Please refer to the links below for more information on these ongoing trials.

In summary, the non-metastatic CRPC disease state is truly an unmet arena in need of beneficial therapy.  This justifies ongoing trial exploration and deserves attention from patients and providers alike.  Patient enrollment to this disease state is often challenging, and we need to work together to improve efforts and eventual outcomes.  We must also recognize that the evolution of novel imaging may gradually be shrinking this non-metastatic CRPC disease state further, making trial accrual a greater challenge for the future.  A subsequent letter from me will focus on novel PET imaging radiotracers with very high sensitivity of detection.

Written by: Evan Yu, MD

Highlighted Trials:
References:
  1. Nelson JB, et al.  Cancer 2008; 113:2478-87.
  2. Miller K, et al.  Prostate Cancer Prostatic Dis 2013; 16:187-92.
  3. Smith MR, et al.  J Clin Oncol 2005; 23:2918-25.
  4. Smith MR, et al.  Lancet 2012; 379:39-46.
  5. Clegg NJ, et al.  Cancer Res 2012; 72:1494-503.
  6. Moilanen AM, et al.  Sci Rep 2015; 5:12007.
  7. Scher HI, et al.  N Engl J Med 2012; 367:1187-97.
  8. Beer TM, et al.  N Engl J Med 2014; 371:424-33.
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