SUMMARY

• ACIS, a phase 3, randomized, double-blind, placebocontrolled, multicenter study, evaluated the efficacy and safety of ERLEADA plus abiraterone acetate with prednisone (AAP) and androgen deprivation therapy (ADT) compared to placebo plus AAP and ADT in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC; N=982). The primary endpoint was radiographic progression-free survival (rPFS) and secondary endpoints included overall survival (OS), time to initiation of cytotoxic chemotherapy, time to pain progression, and time to chronic opioid use.¹
  • Prespecified primary, secondary, and exploratory endpoint results are described in Table: Prespecified Primary, Secondary, and Exploratory Endpoints. At the final analysis for rPFS, after a median follow-up of 54.8 months, a statistically significant improvement in median rPFS was observed in the ERLEADA plus AAP group vs the placebo plus AAP group (24.0 months vs 16.6 months, respectively; HR, 0.70; 95% CI, 0.60-0.83; P<0.0001).
  • Similar median OS was observed in both groups: 36.2 months in the ERLEADA plus AAP group vs 33.7 months in the placebo plus AAP group (HR, 0.95; 95% CI,
  • 0.81-1.11, P=0.50).
  • The incidences of any treatment-emergent adverse events (TEAE) and serious TEAEs were similar between the ERLEADA plus AAP group and the placebo plus AAP group (Table: Summary of Adverse Events).
  • Additional analyses evaluating health-related quality of life (HRQoL)², metastatic stage at presentation³, and subgroup analyses of patients aged ≥75 years or with visceral disease^4,5 are summarized below.
  • Post-hoc analyses revealed that the presence of circulatory tumor deoxyribonucleic acid (ctDNA) and retinoblastoma susceptibility gene (RB1) inactivation at baseline and androgen receptor (AR) aberrations and RB1/tumor protein 53 (TP53) pathway inactivation at the end of study treatment were associated with shorter OS.⁶
• On April 19, 2021, the Janssen Pharmaceutical Companies of Johnson & Johnson announced that regulatory submissions based on the Phase 3 ACIS Study will not be pursued.⁷

CLINICAL DATA

ACIS Study

Saad et al (2021)¹ reported the efficacy and safety of ERLEADA plus AAP compared to placebo plus AAP in patients with chemotherapy-naïve mCRPC (N=982; NCT02257736).

Study Design/Methods

• Phase 3, randomized, double-blind, placebo-controlled, multicenter study
• Patients were randomized 1:1 to receive either:
  • ERLEADA 240 mg orally (PO) once daily (QD) and abiraterone acetate 1,000 mg PO QD with prednisone 5 mg PO twice daily (BID)
  • Placebo and abiraterone acetate 1,000 mg PO QD with prednisone 5 mg PO BID
• All patients received ongoing ADT.
• Patients received 28-day treatment cycles until unequivocal clinical disease progression, unacceptable toxicity, death, or withdrawal of consent.
• Select inclusion and exclusion criteria are described in the Table: Select Inclusion and Exclusion Criteria in the ACIS Study.
• Patients were stratified by presence or absence of visceral metastases, Eastern Cooperative Oncology Group performance status (ECOG PS; 0 or 1), and geographical region (Europe, USA and Canada, or the rest of world).

• Primary endpoint: rPFS (by investigator) defined as the time from date of randomization to date of radiographic progression or death, whichever occurred first
• Secondary endpoints: OS; time to initiation of cytotoxic chemotherapy; time to pain progression; time to chronic opioid use
• Key Exploratory endpoints: time to clinical progression; time to first subsequent anticancer therapy; time to second progression-free survival; confirmed decline of at least 50% in prostate-specific antigen (PSA50) concentration; time to PSA progression; patient-reported outcomes (measured by the Functional Assessment on Cancer Therapy-Prostate [FACT-P] and the Brief Pain Inventory-Short Form [BPI-SF]); safety²
• Post hoc analysis: included undetectable PSA (<0.2 ng/mL at any time during treatment); decline of ≥90% in PSA level; time to first subsequent anticancer therapy

Results

Patient Characteristics

• Patient baseline characteristics were comparable between treatment groups (Table: Select Patient Baseline Characteristics).

Efficacy

• A summary of efficacy results is provided in the Table: Prespecified Primary, Secondary, and Exploratory Endpoints.
• At the primary analysis for rPFS, after a median follow-up of 25.7 months, a statistically significant improvement in median rPFS was observed: 22.6 months in the ERLEADA plus AAP group vs 16.6 months in the placebo plus AAP group (HR, 0.69; 95% CI, 0.580.83; P<0.0001).
  • A blinded independent central review showed 75% concordance in radiographic progression determination with the investigator review, with high positive correlation coefficients in both treatment groups (R=0.833; 95% CI, 0.77-0.88 for ERLEADA plus AAP and R=0.80; 95% CI, 0.75–0.85 for placebo plus AAP).
• At the final analysis for rPFS, after a median follow-up of 54.8 months, consistent improvement in median rPFS was observed with ERLEADA plus AAP compared with placebo plus AAP (24.0 months vs 16.6 months, respectively; HR, 0.70; 95% CI, 0.600.83; P<0.0001).
• At the final analysis for OS, after a median follow-up of 54.8 months, the median OS was 36.2 months in the ERLEADA plus AAP group and 33.7 months in the placebo plus AAP group (HR, 0.95; 95% CI, 0.81-1.11; P=0.50).
• A total of 391 patients (79%) in the ERLEADA plus AAP group and 357 patients (73%) in the placebo plus AAP demonstrated PSA50 (relative response [RR], 1.09; 95% CI, 1.02-1.17; P=0.015). Additionally, 121 patients (25%) in the ERLEADA plus AAP group and 94 patients (19%) in the placebo plus AAP group reached an undetectable PSA level (<0.2 ng/mL) at any time during treatment (RR, 1.28; 95% CI, 1.01-1.62; P=0.040).
• Of the patients who were alive at the time of treatment discontinuation, 273 of 437 patients (62%) in the ERLEADA plus AAP group and 282 of 435 patients (65%) in the placebo plus AAP group received life-prolonging subsequent therapy for prostate cancer.
  • The most common subsequent life-prolonging therapy was chemotherapy, including cabazitaxel or docetaxel (69% [189/273] in the ERLEADA plus AAP group and 71% [200/282] in the placebo plus AAP group). Additionally, 22% of patients (61/273) in the ERLEADA plus AAP group and 20% (56/282) in the placebo plus AAP group received hormonal therapy, including enzalutamide or darolutamide.⁸

HRQoL

• At baseline, the mean FACT-P total score, BPI-SF worst pain, and BPI-SF pain interference in the ERLEADA plus AAP group (n=346, n=485, n=485, respectively) vs placebo plus AAP group (n=317, n=482, n=482, respectively) were 119.8 vs 118.5, 0.92 vs 0.94, and 0.60 vs 0.61, respectively.²
• FACT-P was collected at cycle 1 (baseline) to cycle 6, then every 3 cycles to 12 months after end of treatment. BPI-SF was collected for 7 consecutive days each cycle to end of treatment. The completion rate ranged from 67-75% for FACT-P across 39 treatment cycles and ranged from 6098% for BPI-SF across 43 treatment cycles.²
• No clinically meaningful differences between treatment groups were observed in the FACT-P total score or subscales, BPI-SF worst pain intensity score, or the BPI-SF worst pain interference score.²
• The differences between treatment groups in the median time to deterioration for FACTP total and BPI-SF scores were not statistically significant.²
• For the question “I am bothered by side effects of treatment” (FACT-P GP5), a range of 89-96% of patients in the ERLEADA plus AAP group indicated they were “not at all” or “a little bit” bothered by side effects of treatment.²
• For the question “I have lack of energy” (FACT-P GP1), a range of 65-79% of patients in the ERLEADA plus AAP group indicated they had “not at all” or “a little bit” lack of energy.²
• At the final analysis of rPFS, there was no clinically meaningful decline or worsening in HRQoL, pain, or pain interference.² See Table: PRO Results Prior to rPD and at Last Observation After rPD.
• In general, no pain or mild pain/pain interference was reported during the full treatment duration.²
• In both treatment groups, HRQoL was maintained from baseline until radiographic progression of disease (rPD).²
  • rPD occurred in 257 patients in the ERLEADA plus AAP group and in 330 patients in the placebo plus AAP group.

Safety

• A summary of AEs is described in Table: Summary of Adverse Events.
• The most common TEAEs leading to death were myocardial infarction (n=3), pneumonia (n=2), and pulmonary embolism (n=2) in the ERLEADA plus AAP group and myocardial infarction (n=3), cardiac failure (n=3), cardiorespiratory arrest (n=3), multiple organ dysfunction syndrome (n=2), and sudden death (n=5) in the placebo plus AAP group.⁸

Post-Hoc Exploratory Analysis

• A post-hoc exploratory analysis evaluated the implications of synchronous vs metachronous metastatic stage in docetaxel naïve patients with mCRPC enrolled in the ACIS study. Among 972 patients, 432 had M0, 334 had M1, and 206 were unknown at diagnosis. Results indicated that metastatic stage at presentation had no association with OS in these patients and there was no statistically significant heterogeneity in efficacy of dual AR axis-targeted therapy based on synchronous vs metachronous presentation.³

Subgroup Analysis

• A subgroup analysis evaluated the efficacy and safety of patients aged ≥75 years or with visceral disease (liver, lung, and/or adrenal gland metastasis) enrolled in the ACIS study.^4,5
  • Among patients aged ≥75 years, the median treatment duration in the ERLEADA plus AAP compared with placebo plus AAP was 16.6 months and 15.6 months, respectively.
  • Patients aged ≥75 years or with visceral disease in the ERLEADA plus AAP group had improved OS compared to patients in the placebo plus AAP group. The median rPFS in the ERLEADA plus AAP group among patients aged ≥75 years was 24.7 months vs 16.0 months in the placebo plus AAP group. Among patients with visceral disease, the median rPFS was 16.4 months and 8.3 months in the ERLEADA plus AAP and placebo plus AAP groups, respectively (Table: Efficacy Results in Patients Aged ≥75 Years or with Visceral Disease).
  • TEAEs were similar in patients aged ≥75 years, with visceral disease, and in the overall safety population, with fatigue, hypertension, falls and fractures, skin rash, and seizures higher in the ERLEADA plus AAP group than placebo plus AAP group. Hypertension was more frequent in patients aged ≥75 years (ERLEADA plus AAP, 31.7% vs placebo plus AAP, 17.6%). Additional safety data are summarized in the Table: Safety Results in Patients Aged ≥75 Years or with Visceral Disease.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 16 January 2025.