Page 1 - nmCRPC Clinical Support Tool-June2020
P. 1

Treatment of non-metastatic CRPC



                                               THE AR-TARGETED THERAPIES

























      Treatment of non-metastatic CRPC – THE AR-TARGETED THERAPIES



      Three androgen-receptor (AR)-targeted therapies have been approved in Canada for the treatment of
      non-metastatic castrate-resistant prostate cancer (nmCRPC) – apalutamide, enzalutamide, and darolutamide.
      These treatments may be prescribed for patients diagnosed with high-risk nmCRPC who have the following
      characteristics:
      •  Prostate-specific antigen doubling    Overview of the nmCRPC phase 3 trials:
         time (PSADT) ≤ 10 months                               SPARTAN  1,2        PROSPER  3          ARAMIS  4
      •  CT and bone scan negative                            Apalutamide vs.     Enzalutamide vs.   Darolutamide vs.
         for metastases                         Intervention      Placebo            Placebo             Placebo
      •  Castrate testosterone levels           Sample size        1,207               1,401              1,509
         (< 1.7 nmol/L)                         Primary
                                                endpoint                   MFS (time to metastasis or death)
      Each of the phase 3 clinical trials for the
      three AR-targeted therapies had similar   Eligibility        nmCRPC with PSA > 2 ng/mL and PSADT ≤ 10 months
                                                criteria
      inclusion criteria, and similar positive   Neuro-
      results for the primary endpoint of       condition        History of seizure or any condition      None
                                                                  that may predispose to seizure
      metastasis-free survival (MFS).           exclusions


            nmCRPC Phase 3 Trials: Primary Endpoint – MFS
      MFS Results for the AR-targeted Therapies in the Phase 3 Trials:



                Apalutamide                       Enzalutamide                           Darolutamide
                Apalutamide
                                                    Enzalutamide
                                                                                           Darolutamide
                 (SPARTAN)   2 2                    (PROSPER)   3 3                        (ARAMIS)   4 4
                 (SPARTAN)
                                                                                             (ARAMIS)
                                                      (PROSPER)
                          Median MFS                           Median MFS                                Median MFS
        100               APA + ADT: 40.5 mo  100              ENZA + ADT: 36.6 mo  1.0                  DARO + ADT: 40.4 mo
                          PBO + ADT: 16.2 mo
                                                                                                         PBO + ADT: 18.4 mo
                                                               PBO + ADT: 14.7 mos
                                             90
         90
        Metastasis-free survival (%)  70  Placebo +   Apalutamide + ADT  Metastasis-free survival (%)  70  Placebo +   Enzalutamide  + ADT  Metastasis-free survival   probability  0.7  Darolutamide + ADT
                                                                                 0.9
         80
                                             80
                                                                                 0.8
                                                                                 0.6
         60
                                             60
         50
                                                                                 0.5
                                             50
                                             40
                                                                                 0.4
         40
                                             30
         30
                                                                                 0.3
                                                    ADT
                ADT
         20
                                                                                 0.1
         10
                                             10
                                                 p < 0.001
            p < 0.001
                                                                                    p < 0.001
                                                                                 0.0
          0  HR 0.28 (95% Cl 0.23–0.35)      20 0  HR 0.29 (95% CI 0.24–0.35)    0.2  HR 0.41 (95% CI 0.34–0.50)  Placebo + ADT
           0  4  8 12 16 20 24  28 32 36 40 44  0  3 6 9 12 15 18  21 24 27 30 33 36 39 42  0  4  8  12 16 20 24 28 32 36  40 44   48
                     Months                             Months                                   Months
        No. at risk                      No. at risk                         No. at risk
      APA + ADT 806 713 652 514 398 282 180 96  36  16  3  0  ENZA + ADT    933 865 759 637 528 431 418 328 237 159 87 77 31  4  0  DARO + ADT  955 817  675  506  377  262  189  116  68  37  18  2  0
       PBO + ADT 401 291 220 153  91  58  34  13  5  1  0  0  PBO + ADT 468 420 296 212 157 105 98 64 49 31 16 11  5  1  0  PBO + ADT  554 368  275  180  117  75  50  29  12  4  0  0  0
      ADT = Androgen deprivation therapy; APA = Apalutamide; DARO = Darolutamide; ENZA = Enzalutamide; HR = Hazard ratio; PBO = Placebo
              ADT = Androgen deprivation therapy; APA = Apalutamide;                  1. Smith  MR,  et al. N Engl J Med 2018;378:1408;
              DARO = Darolutamide; ENZA = Enzalutamide;       2. Hussain  M, et al. N Engl J Med 2018;378:2465;   3. Fizazi K,  et al. N Engl J Med 2019;380:1235
              HR = Hazard ratio; PBO = Placebo                                                Slide provided by Dr. Fred Saad
      All three of the phase 3 clinical trials for the AR-targeted therapies have shown a statistically significant overall
      survival benefit for men with nmCRPC. 5,7,9
      Survival Endpoints for the AR-targeted Therapies in the Phase 3 Trials:
                End Points          ARAMIS (DARO vs. PBO)  4,5  SPARTAN (APA vs. PBO) 2,6,7  PROSPER (ENZA vs. PBO)
                                                                                                                   8.9
                (median)                    n = 1,508                   n = 1,207                   n = 1,401
       OS                           NR vs. NR                   73.9 vs. 59.9 mos           67.0 vs. 56.3 mos
                                    (HR = 0.69; p = 0.003)      (HR = 0.784; p = 0.0161)    (HR = 0.73; p = 0.0011)
       PFS                          36.8 mos vs. 14.8 mos       40.5 mos vs. 14.7 mos                  –—
                                    (HR = 0.38, p < 0.001)      (HR = 0.29; p < 0.001)
       PFS2                                    –—               55.6 vs. 43.8 mos                      –—
                                                                (HR = 0.55; p < 0.0001)
      APA = Apalutamide; DARO = Darolutamide; ENZA = Enzalutamide; HR = Hazard ratio; NR = Not reached; OS = Overall survival; PBO = Placebo; PFS = Progression-free
      survival; PFS2 = Second-progression-free survival
   1   2