Table 1 Summary of pivotal trials for second-generation ARIs in nmCRPC.

From: Treatment of nonmetastatic castration-resistant prostate cancer: focus on second-generation androgen receptor inhibitors

 

SPARTAN (NCT01946204) [15, 42, 61]

PROSPER (NCT02003924) [14, 45, 62]

ARAMIS (NCT02200614) [16, 48, 63]

Study description

Randomized phase 3 study to evaluate the safety and efficacy of apalutamide vs. placebo in patients with nmCRPC (N = 1207)

Randomized phase 3 study to evaluate the safety and efficacy of enzalutamide vs placebo in patients with nmCRPC (N = 1401)

Randomized phase 3 study to evaluate the safety and efficacy of darolutamide vs placebo in patients with nmCRPC (N = 1509)

Patient population

nmCRPC with PSADT ≤ 10 months

nmCRPC with BL PSA ≥ 2 ng/mL and PSADT ≤ 10 months

nmCRPC with PSADT ≤ 10 months

 

No lesions detectable by CT/MRI or bone scan

No lesions detectable by CT/MRI and bone scan and no history of seizure

No lesions detectable by CT/MRI or bone scan

Primary analysis

   

Median follow-up

20.3 months

Enzalutamide: 18.5 months

Placebo: 15.1 months

17.9 months

Primary endpoint (drug vs. placebo)

Median MFS, assessed from randomization until radiographic progression by blinded independent central review or death

Median MFS, assessed from randomization until radiographic progression by blinded independent central review or death

Median MFS, assessed from randomization until radiographic progression by blinded independent central review or death

40.5 vs. 16.2 months; HR 0.28;

95% CI 0.23–0.35; P < 0.001

36.6 vs. 14.7 months; HR 0.29;

95% CI 0.24–0.35; P < 0.001

40.4 vs. 18.4 months; HR 0.41;

95% CI 0.34–0.50; P < 0.001

Secondary endpoints evaluated in a hierarchical order (drug vs. placebo)

Median PFS:

40.5 vs. 14.7 months; HR 0.29;

95% CI: 0.24–0.36; P < 0.001

Median time to PSA progression:

37.2 vs. 3.9 months; HR 0.07;

95% CI 0.05–0.08; P < 0.001

Median OS:

NR vs. NR; HR 0.71;

95% CI 0.50–0.99; P = 0.045

Median time to symptomatic progression:

NR vs. NR; HR 0.45;

95% CI 0.32–0.63; P < 0.001

Median time to first use of new antineoplastic therapy:

39.6 vs. 17.7 months; HR 0.21;

95% CI 0.17–0.26; P < 0.001

Median time to pain progression:

40.3 vs. 25.4 months; HR 0.65;

95% CI 0.53–0.79

Median OS:

NR vs. 39.0 months; HR 0.70;

95% CI 0.47–1.04; P = 0.07

Median OS:

NR vs. NR; HR 0.80;

95% CI 0.58–1.09; P = 0.15

Median time to first use of cytotoxic chemotherapy:

NR vs. 38.2 months; HR 0.43;

95% CI 0.31–0.60

Median time to first cytotoxic chemotherapy:

NR vs. NR; HR 0.44;

95% CI 0.29–0.66

Median time to first SSE:

NR vs. NR; HR 0.43;

95% CI 0.22–0.84

Median PFS:

36.8 vs. 14.8 months; HR 0.38;

95% CI 0.32–0.45

Median time to PSA progression:

33.2 vs. 7.3 months; HR 0.13;

95% CI 0.11–0.16

Final analysis

(N = 1207)

(N = 1401)

(N = 1509)

Median follow-up

52.0 months

48.0 months

29.0 months

Secondary endpoints (drug vs. placebo)

Median OS:

73.9 vs. 59.9 months; HR 0.78;

95% CI 0.64–0.96; P = 0.016

Median OS:

67.0 vs. 56.3 months; HR 0.73;

95% CI 0.61–0.89; P = 0.001

Median OS:

NR vs. NR; HR 0.69;

95% CI 0.53–0.88; P = 0.003

Median time to cytotoxic chemotherapy:

NR vs. NR; HR 0.63;

95% CI 0.49–0.81; P = 0.0002

Median time to use of cytotoxic chemotherapy:

NR vs. NR; HR 0.54;

95% CI 0.44–0.67

Median time to first cytotoxic chemotherapy:

NR vs. NR; HR 0.58;

95% CI 0.44–0.76; P < 0.001

Median time to symptomatic progression:

NR vs. NR; HR 0.57;

95% CI 0.44–0.73; P < 0.0001

Median time to first use of new subsequent antineoplastic therapy:

66.7 vs. 19.1 months; HR 0.29;

95% CI 0.25–0.34

Median time to pain progression:

40.3 vs. 25.4 months; HR 0.65;

95% CI 0.53–0.79; P < 0.001

Median time to PSA progression:

40.5 vs. 3.7 months; HR 0.07;

95% CI 0.06–0.09; P < 0.0001

Chemotherapy-free survival:

58.3 vs. 41.6 months; HR 0.62;

95% CI 0.52–0.72

Median time to first SSE:

NR vs. NR; HR 0.48;

95% CI 0.29–0.82; P = 0.005

Median time to second progression:

55.6 vs. 41.2 months; HR 0.55;

95% CI 0.46–0.66; P < 0.0001

  

HRQoL outcomes at primary analysis (drug vs. placebo)a

Change from baseline in mean ± SE

FACT-P total score:

−0.99 ± 0.98 vs. −3.29 ± 1.97

BPI-SF (pain severity):

time to progression

36.8 months vs. NR; HR 0.75;

95% CI 0.57–0.97; P = 0.028

BPI-SF (LSM time-adjusted AUC mean changes from baseline):

pain interference:

1.1 vs. 1.3 points; difference −0.2;

95% CI −0.3 to −0.1

Change from baseline in mean ± SE

EQ VAS score:

1.44 ± 0.87 vs. 0.26 ± 1.75

FACT-P total score:

time to deterioration

22.1 vs. 18.4 months; HR 0.83;

95% CI 0.69–0.99; P = 0.037

Pain severity:

1.3 vs. 1.4 points; difference −0.2;

95% CI −0.3 to −0.1

EORTC QLQ-PR25:

time to deterioration

FACT-P total score (LSM time-adjusted AUC mean changes from baseline):

112.9 vs. 111.6 points; difference 1.3;

95% CI 0.4–2.1

Bowel symptoms and function:

33.2 vs. 25.9 months; HR 0.72;

95% CI 0.59–0.89; P = 0.0018

FACT-P PCS total score:

time to deterioration

11.1 vs. 7.9 months; HR 0.80;

95% CI 0.70–0.91; P = 0.0005

Hormonal treatment-related symptoms:

33.2 vs. 36.8 months; HR 1.29;

95% CI 1.02–1.63; P = 0.035

EORTC QLQ-PR25:

time to deterioration

Urinary symptoms:

36.9 vs. 25.9 months; HR 0.58;

95% CI 0.46–0.72; P < 0.0001

Bowel symptoms:

18.4 vs. 11.5 months; HR 0.78;

95% CI 0.66–0.92; P < 0.01

Urinary symptoms:

25.8 vs. 14.8 months; HR 0.64;

95% CI 0.54–0.76; P < 0.01

  1. ADT androgen-deprivation therapy, AUC area under the curve, BL baseline, BPI-SF Brief Pain Inventory Short Form, C30 30-item core questionnaire, CI confidence interval, CRPC castration-resistant prostate cancer, CT computerized tomography, EORTC QLQ European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire, EQ VAS European Quality of Life Visual Analogue Scale, FACT-P Functional Assessment of Cancer Therapy-Prostate, FACT-P PCS Functional Assessment of Cancer Therapy-Prostate, prostate cancer subscale, HR hazard ratio, HRQoL health-related quality of life, LSM least-squares mean, mCRPC metastatic castration-resistant prostate cancer, MFS metastasis-free survival, mHSPC metastatic hormone-sensitive prostate cancer, mPC metastatic prostate cancer, MRI magnetic resonance imaging, nmCRPC nonmetastatic castration-resistant prostate cancer, nmPC nonmetastatic prostate cancer, NE not estimable, NR not reached, OS overall survival, PBO placebo, PC prostate cancer, PFS progression-free survival, PR25 prostate cancer-specific 25-item questionnaire, QoL quality of life, rPFS radiographic progression-free survival, SSE symptomatic skeletal event.
  2. aOnly significant results are reported in this table.
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