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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, darolutamide, and enzalutamide.
      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         ARAMIS 3           PROSPER 4
      •  CT and bone scan negative              Intervention  Apalutamide vs.     Darolutamide vs.   Enzalutamide vs.
         for metastases                                           Placebo            Placebo             Placebo
                                                Sample size        1,207               1,509              1,401
      •  Castrate testosterone levels           Primary
         (< 1.7 nmol/L)                         endpoint                   MFS (time to metastasis or death)
                                                Eligibility
      Each of the phase 3 clinical trials for the   criteria       nmCRPC with PSA > 2 ng/mL and PSADT ≤ 10 months
      three AR-targeted therapies had similar   Neuro-      History of seizure or any              History of seizure or any
      inclusion criteria, and similar positive   condition    condition that may      None           condition that may
      results for the primary endpoint of       exclusions   predispose to seizure                  predispose to seizure
      metastasis-free survival (MFS).
                                               All patients continued to receive androgen-deprivation therapy




      MFS Results for the AR-targeted Therapies in the Phase 3 Trials:
            nmCRPC Phase 3 Trials: Primary Endpoint – MFSnmCRPC Phase 3 Trials: Primary Endpoint – MFS
 nmCRPC Phase 3 Trials: Primary Endpoint – MFS
      Increase in median MFS of 22 to 24 months with ARAT treatment


                Apalutamide                           Darolutamide                            Enzalutamide
                                                      Darolutamide
                Apalutamide
 Apalutamide   Enzalutamide                       Enzalutamide  3                        Darolutamide 4                             Darolutamide
                                                          Apalutamide
                                                                                             Enzalutamide
                 (SPARTAN)
                                                        (ARAMIS)
                                                                                               (PROSPER)
                            2
                                                       (ARAMIS)
 (SPARTAN) 2    (PROSPER)   3 2                     (PROSPER)   3  4    2                  (ARAMIS)   4   3                           (ARAMIS)   4
                                                           (SPARTAN)
                 (SPARTAN)
                                                                                               (PROSPER)
                                                                     Median MFS
 Median MFS               Median MFS                           Median MFS Median MFS                     Median MFS                                Median MFS
                           Median MFS
                                                                                                          Median MFS
                                                                     DARO + ADT: 40.4 mo
 100  APA + ADT: 40.5 mo  100  APA + ADT: 40.5 mo  100  100    ENZA + ADT: 36.6 mo  1.0  100             DARO + ADT: 40.4 mo  1.0                  DARO + ADT: 40.4 mo
                                                                     APA + ADT: 40.5 mo
         100
                                                                                                          ENZA + ADT: 36.6 mo
                           ENZA + ADT: 36.6 mo
                                                                                                                                                   PBO + ADT: 18.4 mo
                                                                     PBO + ADT:
 PBO + ADT: 16.2 mo
                                                                                                         PBO + ADT: 18.4 mo
                                                                     PBO + ADT:  18.4 mo
                          PBO + ADT: 16.2 mo
                           PBO + ADT: 14.7 mos
                                                               PBO + ADT: 14.7 mos 16.2 mo
                                                                              Metastasis-free survival
                                                                                                          PBO + ADT: 14.7 mos
 Metastasis-free survival (%)  70  Placebo +   Apalutamide + ADT  Metastasis-free survival (%) Metastasis-free survival (%)  70 70  Placebo +   Apalutamide + ADTT  Metastasis-free survival  Metastasis-free survival (%) 1.0  Metastasis-free survival (%)  70  ADT  Enzalutamide  + ADTmide + ADT 0.7  Metastasis-free survival (%)  70  Placebo +   Darolutamide + ADT  Metastasis-free survival   probability  0.7  Darolutamide + ADT
 90
         90 90
                                                    90
                                                                                                                           0.9
                                             0.9
                                                                                        90
                                                                                 0.9
                                             90
         80 80
 80
                                                    80
                                             0.8
                                                                                        80
                                             80
                                                                                                                           0.8
                                                                                 0.8
                           Enzalutamide  + AD
                                                                      Apaluta
                                                                                                          Enzalutamide  + ADT
                                            probability
                                             0.7
                                                                                probability
                                             70
                                                                    Darolutamide + ADT
 60
                                             0.6
                                                    60
         60 60
                                                                                 0.6
                                             60
                                                                                        60
                                                                                                                           0.6
                                             0.5
 50
         50 50
                                             50
                                                                                 0.5
                                                    50
                                                                                                                           0.5
                                                                                        50
                                             0.4
 40
         40 40
                                                                                                                           0.4
                                                                                 0.4
                                                    40
                                             40
                                                                                        40
                                                    Placebo +  Placebo +
                Placebo +
 30
                                             0.3
                                                                                 0.3
                                                                                                                           0.3
         30 30
                                                    30
                                                                                        30
                                             30
                ADT
 ADT
                ADT
                                                                                               ADT
                                                    ADT
 20
                                             0.2
                                                                                        20
                                                    20
                                             20
                                                 HR 0.29 (95% CI 0.24–0.35)0.23–0.35) Placebo + ADT
                                                       HR 0.28 (95% Cl
             HR 0.29 (95% CI 0.24–0.35)
                                                                                           HR 0.29 (95% CI 0.24–0.35)
                                             0.1
 10
                                                                                 0.1
         10 10
                                                    10
                                                                                        10
                                                                                                                           0.1
                                             10
 p < 0.001
            p < 0.001
                                                                                           p < 0.001
             p < 0.001
                                                 p < 0.001   p < 0.001
                                                p < 0.001
                                                                                                                               p < 0.001
                                                                                    p < 0.001
                                                                                                                           0.0
 0  HR 0.28 (95% Cl 0.23–0.35)  20 20  HR 0.28 (95% Cl 0.23–0.35)  0.0  HR 0.41 (95% CI 0.34–0.50)  0.2  HR 0.41 (95% CI 0.34–0.50)  Placebo + ADT  0.2  HR 0.41 (95% CI 0.34–0.50)  Placebo + ADT
          0 0
                                                     0
                                                                                 0.0
                                                                                         0
                                              0
                                                                       40
                             30 33 36 39
 0  4  8 12 16 20 24  28 32 36 40 44  0 30  4 6 9 12 15 18 21  28 32 36 40 44 42  0 0  3 6 9 12 15 18 8 12 16 20 240 12 16 20 24 28 32 36 28 3244   48  0  4  8  12 16 20 24 28 32 36 27 40 44   48 39 42  0  4  8  12 16 20 24 28 32 36  40 44   48
                8 12 16 20 24 24 27
                                                  4
                                                    8
                                                                                                           30 33 36
                                                                                            3 6 9 12 15 18
                                                                                                      21 24
                                                                                          0
                                                                 30 33 36 39 42 36 40 44
                                                           21 24 27
                                                         4
 Months              Months                             Months Months                            Months                                     Months
                                                                Months
                     Months
                                                                                                   Months
 No. at risk  No. at risk                No. at risk  No. at risk            No. at risk  No. at risk                   No. at risk
        No. at risk
                                         No. at risk
                                          ENZA + ADT    933 865 759 637 528 431 418 328 237 159 87 77 31 96 183768116189262377506
 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  36  1631  34  0 0  DARO + ADT  955 817  675  4  0 36  2 16  0 DARO + ADT  955 817  675  506 865 759  262 528 189 431 418  68 237 37 159  18 87 77 31  0 4  0  DARO + ADT  955 817  675  506  377  262  189  116  68  37  18  2  0
                                                                                                              2
      APA + ADT 806 713 652 514 398 282 180 96 159 87 77
                                                                               0
                                                                             3
                                                 APA + ADT 806 713 652 514 398 282 180
                                                                                                    116 328
                                                                                             377 637
                                                                                    ENZA + ADT    933
                                                 PBO + ADT 401 291 220 1535075117180
                                                                               0
 PBO + ADT 401 291 220 153  91  58  34  13  5  1  0  0  PBO + ADT 468 420 296 212 157  91  58  34  13  5  1 5  01  0 0  PBO + ADT  554 368  275  91 29 58 12  5 13 04  1  0 5  0 1  0 0 PBO + ADT  554 368  275 468 420 296 212 157 105 98 64 49 31 16 11 0 5  0 1  0  PBO + ADT  554 368  275  180  117  75  50  29  12  4  0  0  0
                                          PBO + ADT 468 420 296 212 157 105 98 64 49 31 16 11 34
                                                                                             117
                                                                                                           0
                                                                                          180
                                                                                                  50
                                                                                                         4
                                                                                               75
                                                                                                    29
                                                                                                      12
       PBO + ADT 401 291 220 153 105 98 64 49 31 16 11
                                                                                     PBO + ADT
      ADT = Androgen deprivation therapy; APA = Apalutamide; DARO = Darolutamide; ENZA = Enzalutamide; HR = Hazard ratio; PBO = Placebo
                                                         ADT = Androgen deprivation therapy; APA = Apalutamid
 ADT = Androgen deprivation therapy; APA = Apalutamide;   ADT = Androgen deprivation therapy; APA = Apalutamide;   1. Smith  MR,  et al. N Engl J Med 2018;378:1408;     1. Smith  MR,  et al. N Engl J Med 2018;378:1408;   e;   1. Smith  MR,  et al. N Engl J Med 2018;378:1408;
 DARO = Darolutamide; ENZA = Enzalutamide;   DARO = Darolutamide; ENZA = Enzalutamide;  Engl J Med 2018;378:2465;   3. Fizazi K,  et al. N Engl J Med 2019;380:1235
                                                         DARO = Darolutamide; ENZA = Enzalutamide;
                           2. Hussain  M, et al. N
                                                              2. Hussain  M, et al. N Engl J Med 2018;378:2465;   3. Fizazi K,  et al. N Engl J Med 2019;380:12352. 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  HR = Hazard ratio; PBO = Placebo  HR = Hazard ratio; PBO = Placebo  Slide provided by Dr. Fred Saad   Slide provided by Dr. Fred Saad
                                                          Slide provided by Dr. Fred Saad
      Overall Survival for the AR-targeted Therapies in the Phase 3 Trials:
      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
               Apalutamide                             Darolutamide                           Enzalutamide
                (SPARTAN)   5                            (ARAMIS)  6                           (PROSPER)  7
                      Median OS                               Median OS                              Median OS
                      APA + ADT: 73.9 mos                     DARO + ADT: NR                         ENZA + ADT: 67.0 mos
                      PBO + ADT: 59.9 mos                     PBO + ADT: NR                          PBO + ADT: 56.3 mos
                                          100
                                                                                 100
         100
                                          90
                                                                                 90
                                          80                      Darolutamide
         80                                                                      80
                                          70 60                 Placebo          70
        Overall Survival (%)  60 40  Placebo  Apalutamide  Overall Survival (%)  50 40  Overall Survival (%)  60 50 40  Placebo Enzalutamide
         20                               30 20                                  30 20
            HR 0.78 (95% CI 0.64–0.96)    10  HR 0.69 (95% C 0.53–0.88)          10  HR 0.73 (95% CI 0.61–0.89)
            p = 0.016                        p = 0.003                             p = 0.001
          0                                0                                      0
          0  4  8  12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72  76  0  4  8  12  16  20  24  28  32  36  40  44  48  52  56  60  0  4  8  12  16  20  24  28  32  36  40  44  48  52  56  60  64  68  72
                    Months from randomisation         Months since Randomization                    Months
     No. at Risk                     No. at Risk                             No. at Risk
     Apalutamide    806 791 774 758 739 717 691 658 625  593 558 499 376 269 181 100  47   19    4      0  Darolutamide  955  932  908  863  816  771  680  549  425  293  214  129  69  37  12  0  Enzalutamide 933  926  910  897  874  850  822  782  700  608  517  424  327  244  169  89  33  4  0
     Placebo            401 392 385 373 358 339 328 306 286  263 240 204 156 114  82   38   21    6     2      0  Placebo  554  530  497  460  432  394  333  261  182  130  93  54  28  16  4  0  Placebo  468  467  459  444  428  404  381  363  321  274  219  177  140  106  64  30  16  3  0
      ADT = Androgen deprivation therapy; APA = Apalutamide; DARO = Darolutamide; ENZA = Enzalutamide; HR = Hazard ratio; NR = Not reached; PBO = Placebo
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