SUMMARY

• ACIS, a phase 3, randomized, double-blind, placebo-controlled, 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 endpoints 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, 0.600.83; 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, 0.811.11; 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, association of blood biomarkers with clinical outcomes³, metastatic stage at presentation⁴, and subgroup analyses patients aged ≥75 years or with visceral disease^5,6 have been reported.
  • 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
• ARN-509-001, a phase 2, open-label study, evaluated the safety and efficacy of ERLEADA in patients with mCRPC who either received or did not receive prior therapy with AAP (N=46). The proportion of patients with prostate-specific antigen (PSA) decline ≥50% (PSA50) at 12 weeks was 88% (95% CI, 69-97) and 22% (95% CI, 6-48) in patients who had not received prior therapy with AAP (AAP-naïve cohort) and those who had received prior therapy (post-AAP cohort), respectively. The most common AEs were fatigue (60%), nausea (56%), and abdominal pain (48%) in the AAP-naïve cohort and fatigue (52%), diarrhea (38%), and nausea (33%) in the post-AAP cohort.⁸
• In a phase 2 study, the efficacy and safety of ERLEADA and AAP with or without ipilimumab or cabazitaxel and carboplatin (CABCARB) in patients with mCRPC based on initial response to 8 weeks of ERLEADA and AAP therapy was evaluated. After a median follow-up of 48 months, the median OS (95% CI) for patients receiving ERLEADA and AAP (Mod2A), ERLEADA and AAP with ipilimumab (Mod2B), and ERLEADA and AAP with CABCARB (Mod3) was 44.3 months (38.1-47.7), 41.4 months (33.3-not reached [NR]), and 18.7 months (14.3-36.3), respectively. Serious adverse events (SAEs) occurred in 3 (4.7%) patients, 21 (33%) patients, and 6 (10.2%) patients in Mod2A, Mod2B, and Mod3, respectively. In Mod3, 1 death due to neutropenic sepsis was reported.^9,10
  • Additionally, results from an assessment of aggressive variant prostate cancer molecular signature and androgen indifference have been reported.¹¹
• Efficacy results have been reported for the ongoing, phase 2, prospective PANTHER study (NCT03098836) evaluating the use of ERLEADA and AAP in Black (n=43) and White (n=50) patients with mCRPC (Table: Efficacy Outcomes in Black and White Patients in the PANTHER Study).^12,13

CLINICAL DATA

Phase 3 Study

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 PSA50; 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

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 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 updated 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 (79%) patients in the ERLEADA plus AAP group and 357 (73%) patients in the placebo plus AAP demonstrated PSA50 (relative response [RR], 1.09; 95% CI, 1.02-1.17; P=0.015). Additionally, 121 (25%) patients in the ERLEADA plus AAP group and 94 (19%) patients 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.¹⁴

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.¹⁴

Phase 2 Studies

Rathkopf et al (2017)⁸ reported results of the ARN-509-001 study evaluating the safety and efficacy of ERLEADA in patients with mCRPC who either received or did not receive prior therapy with AAP (N=46).

Study Design/Methods

• Phase 2, open-label, multicenter study
• Patients with mCRPC were enrolled in 1 of 2 cohorts:
  • AAP-naïve cohort (n=25): patients who were not treated previously with AAP and who had disease progression, defined by a rising PSA ≥2 ng/mL within 2 weeks of study enrollment or measurable disease (new or progressive tissue disease on computed tomography [CT]/magnetic resonance imaging [MRI] or ≥2 new bone lesions on radiographic scans)
  • Post-AAP cohort (n=21): patients who received ≥6 months of AAP therapy prior to disease progression
• Results from a third cohort of patients with non-mCRPC were reported separately.¹⁵
• Patients received ERLEADA 240 mg PO QD until evidence of both PSA progression and radiographic progression or clinical progression alone, development of unacceptable toxicity, or withdrawal of consent.
• Select inclusion criteria: pathologically proven prostate adenocarcinoma; receiving continuous ADT with a gonadotropin-releasing hormone analogue (GnRHa) or orchiectomy; castrate levels of serum testosterone (≤50 ng/dL) within 4 weeks of study enrollment; ECOG PS 0-1
• Select exclusion criteria: previous treatment with enzalutamide, ketoconazole, or chemotherapy for mCRPC; history of seizure or conditions that predispose to seizures
• Primary endpoint: proportion of patients with PSA50 at 12 weeks (or earlier for those who discontinued therapy)
• Secondary endpoints: time to PSA progression, progression-free survival, objective response rate

Results

Patient Characteristics

• Patient baseline characteristics are described in Table: Select Patient Baseline Demographics.

Efficacy

• Three patients in the post-AAP cohort were excluded from the efficacy analysis for either failing to meet the criteria for progressive metastatic disease (n=1) or not receiving abiraterone acetate for ≥6 months (n=2).
• Median time on treatment was 21 months (range, 2.6-37.5 months) for the AAP-naïve cohort and 4.9 months (range, 1.3-23.2 months) for the post-AAP cohort.
• The proportion of patients with PSA50 at 12 weeks was 88% (95% CI,
  69-97) and 22% (95% CI, 6-48) in the AAP-naïve and post-AAP cohorts, respectively (Table: Efficacy Outcomes).
• A total of 80% and 64% of AAP-naïve and 43% and 10% of post-AAP patients remained on treatment for ≥6 months and ≥12 months, respectively.

Safety

• The most common TEAEs were fatigue (n=15; 60%), nausea (n=14; 56%), and abdominal pain (n=12; 48%) in the AAP-naïve cohort and fatigue (n=11; 52%), diarrhea (n=8; 38%), and nausea (n=7; 33%) in the post-AAP cohort.
• Serious AEs were reported in 8 (32%) AAP-naïve patients and 6 (29%) post-AAP patients. No seizures were reported.
• Seven (28%) patients in the AAP-naïve cohort and 8 (38%) patients in the post-AAP cohort required dose modifications, mostly due to AEs.
• Treatment discontinuation due to an AE occurred in 3 patients in the AAP-naïve cohort and 1 patient in the post-AAP cohort.

Viscuse et al (2022)⁹ reported results from the DynAMo study evaluating the efficacy and safety of ERLEADA and AAP with or without ipilimumab or CABCARB in patients with mCRPC based on initial response to 8 weeks of ERLEADA and AAP therapy (N=195; NCT02703623).

Study Design/Methods

• Phase 2, open-label study
• All patients received ERLEADA and AAP for 8 weeks (Mod1). Patients who achieved a PSA50 from baseline and circulating tumor cell (CTC) ≤5/7.5 mL at week 8 were considered satisfactory (S) responders; patients who did not were considered unsatisfactory (US) responders.
• S patients were then randomized to receive one of two treatments:
  • ERLEADA PO QD, abiraterone acetate PO QD, and prednisone PO BID (Mod2A)¹⁰
  • ERLEADA PO QD, abiraterone acetate PO QD, prednisone PO BID, and ipilimumab IV, up to 4 cycles (Mod2B)¹⁰
• US patients continued ERLEADA and AAP with up to 10 cycles of CABCARB (Mod3).
• All patients received ERLEADA and AAP until progression.
• Select exclusion criteria: any prior treatment with ipilimumab; treatment with any other systemic therapy for prostate cancer within 28 days of cycle 1 day 1, including investigational products (exceptions were luteinizing hormone-releasing hormone [LHRH] agonists, LHRH antagonists, bisphosphonates, and RANK-ligand inhibitors); treatment within 12 months of cycle 1 day 1 with any CYP17-lyase inhibitor, any second generation androgen receptor (AR) antagonist, cabazitaxel, or carboplatin; patients who experienced disease progression while on treatment or within 3 months of discontinuation of any CYP17-lyase inhibitor, any second generation AR antagonist, cabazitaxel, or carboplatin¹⁰
• OS was calculated from entry into Mod2 or Mod3.

Results

Patient Characteristics

• Of 195 enrolled patients, 128 (67%) patients were allocated to S and randomized to Mod2A (n=64) and Mod2B (n=64).
• In Mod3 (n=64), 59 patients were treated with CABCARB on study.
• In Mod1, 3 patients went off study without clinical decline.
• US patients were more likely than S patients to have had de novo metastases (33% vs 59%; P<0.001), Response Evaluation Criteria in Solid Tumor (RECIST) measurable disease (23% vs 42%; P=0.01), and liver metastases (3% vs 42%; P=0.01).
• Based on historical data, the estimated median OS for patients in Mod2 and Mod3 were 36 months and 16 months, respectively.

Efficacy

• After a median follow-up of 48 months, the median OS (95% CI) for patients in Mod2A, Mod2B, and Mod3 was 44.3 months (38.1-47.7), 41.4 months (33.3-NR), and 18.7 months (14.3-36.3), respectively.

Safety

• SAEs occurred in 3 (4.7%) patients, 21 (33%) patients, and 6 (10.2%) patients in Mod2A, Mod2B, and Mod3, respectively.
• In Mod3, 1 death due to neutropenic sepsis was reported.

George et al (2024)¹² and (2023)¹³ reported results of the ongoing PANTHER study evaluating the efficacy and safety of ERLEADA and AAP in patients with mCRPC stratified by race (Black, n=43; White, n=50).

Study Design/Methods

• Phase 2, prospective, open-label, multicenter, parallel cohort study
• All patients were treated with ERLEADA 240 mg PO QD, abiraterone acetate 1000 mg PO QD, and prednisone 5 mg PO BID until unacceptable toxicity, disease progression, or 2 years,¹⁶ at which point patients were switched to standard of care.
• Primary endpoint: rPFS
• Secondary endpoints: time to PSA progression, OS, PSA response

Results

Patient Demographics

• Key baseline characteristics for each cohort are summarized in Table: Select Baseline Patient Characteristics.

Efficacy

• Efficacy outcomes for both cohorts are summarized in Table: Efficacy Outcomes in Black and White Patients in the PANTHER Study. In the long term efficacy analysis, the median follow-up was 56 months and 62 months for the Black and White cohort, respectively.

Safety

• Safety results were not reported.

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 May 2024. Summarized in this response are relevant data from phase 3 and phase 2 studies in patients with mCRPC.