With Apalutamide's Regulatory Approval for Non-Metastatic (M0) CRPC, Why Not Move Agents Even Earlier into the Castration-Sensitive Biochemically-Recurrent Disease State?

One year ago, in this column, I highlighted the non-metastatic (M0) castration-resistant prostate cancer (CRPC) disease state as a fruitful area for clinical trial exploration.1  As part of that article, I emphasized the concept of testing low toxicity, high efficacy agents from metastatic CRPC in earlier disease states.  Two of the randomized, phase 3 trials have just came out and the results are quite impressive.

Enzalutamide, a pure androgen receptor (AR) antagonist, already regulatory approved for metastatic CRPC, offers metastasis-free survival (MFS) benefit over placebo in the PROSPER randomized, phase 3 trial for patients with high-risk non-metastatic CRPC.  High-risk was determined by short PSA doubling time ≤10 months, with approximately ¾ of the population with PSA doubling time <6 months.2  The difference was dramatic with MFS of 36.6 mos for the apalutamide arm vs. 14.7 mos for the placebo arm (HR 0.29; p<0.0001).  Time to first use of new antineoplastic therapy was a median of 39.6 with enzalutamide vs. 17.7 months with placebo.  Another pure AR antagonist, apalutamide, also showed impressive MFS benefit in the randomized, phase 3 SPARTAN trial.3  With apalutamide, median MFS was 40.5 months vs. 16.2 months with placebo (HR 0.28; p<0.0001).  There was also a meaningful 55% risk reduction in time to symptomatic progression with apalutamide over placebo.  Overall survival in both of these trials is not significant, as the data is far from mature.  Adverse events from both of these compounds were acceptable and consisted of fatigue, rash, falls and fractures at low rates.  Meanwhile, the ARAMIS, randomized phase 3 trial of darolutamide (ODM-201) versus placebo is still ongoing for this patient population.  This agent has activity as an AR antagonist, with the unique property of inhibiting some known AR mutants.4 

Given the trends of moving agents like abiraterone, docetaxel, enzalutamide and apalutamide into earlier disease states, the next earlier disease state would be castration-sensitive biochemically-recurrent prostate cancer.  The challenge with performing trials in this disease state is the extreme clinical heterogeneity that exists for this population.  For example, median overall survival for the patients in the PR7 randomized control trial of intermittent vs. continuous androgen deprivation therapy was approximately 9 years,5 making clinical trial design with the endpoint of overall survival extremely challenging.  Appropriate patient selection of those with high-risk disease and identification of surrogate endpoints will ultimately be important for eventual regulatory approval.

The recent ICECaP meta-analysis of 28 trials of patients with localized prostate cancer helped with validating MFS as a surrogate of overall survival.6  This likely aided in the acceptability of MFS as an approvable endpoint, and we recently saw the FDA approval of apalutamide in the United States on February 14, 2018.  However, an even earlier endpoint would be ideal.  At the University of Washington, our group has performed a single institution retrospective analysis of patients who received 6-12 months of androgen deprivation therapy and found detectable PSA one year after completion of therapy to associate with risk of metastasis (p=0.006) and prostate cancer-specific death (p=0.028).7  Although these findings require confirmation, the field needs to consider earlier endpoints like this to try to establish surrogates for meaningful outcomes.  This will only aid future clinical trial design and facilitate our ability to bring efficacious agents more rapidly to our patients.

Although there are many ongoing clinical trials for patients with biochemically-recurrent prostate cancer, I highlight a few below that are significant efforts with agents that are felt to have promise against prostate cancer.  This includes the EMBARK trial, a large 1860 patient randomized control trial that is attempting to introduce enzalutamide even earlier in the treatment paradigm.  This trial is using MFS as the primary endpoint.  The Alliance Foundation is also performing a randomized phase 3 trial in this setting, testing degarelix, apalutamide and abiraterone, with PSA as the primary progression endpoint.  Finally, our field is moving towards use of PARP inhibitors, especially in patients with homologous recombination deficiency.  An open-label phase 2 trial with olaparib is evaluating both biomarker unselected and selected patient populations, using PSA decline as the primary endpoint.  All three of the above trials are highlighted below.

Highlighted Trials

Written by: Evan Yu, MD


  1. Yu, Evan. “Non-Metastatic castration-Resistant prostate cancer, a disease state misnomer that is a seriously unmet therapeutic need.” UroToday, 14 Mar. 2017
  2.  Hussain M et al.  J Clin Oncol 36; 2018 (suppl 6S; abstr 3).
  3. Smith MR et al.  N Engl J Med 2018; Epub February 8, 2018.
  4.  Moilanen AM et al.  Sci Rep 2015; 5:12007.
  5.  Crook JM et al.  N Engl J Med 2012; 367:895-903.
  6. Xie W et al.  J Clin Oncol 2017; 35:3097-104.
  7. Lim DM et al.  J Clin Oncol 36; 2018 (suppl 6S; abstr 207).