Adverse Event - Hematologic Effects

summary

• This response includes relevant data from the pivotal studies of ZYTIGA: COU-AA-301, COU-AA-302, and LATITUDE.
• COU-AA-301 (NCT00638690) was a phase 3, randomized, double-blind, placebo-controlled, multinational study of ZYTIGA plus prednisone vs placebo plus prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) and disease progression after docetaxel-based chemotherapy (N=1195).¹
  • The median follow-up was 12.8 months at the time of the interim analysis. The final analysis published by Fizazi et al (2012)² reported a median follow-up of 20.2 months. Grade 3 and 4 hematological adverse event (AE) rates for both ZYTIGA plus prednisone and placebo plus prednisone groups were consistent.²
• COU-AA-302 (NCT00887198) was a phase 3, randomized, double-blind, placebo-controlled, multinational study of ZYTIGA plus prednisone vs placebo plus prednisone in asymptomatic or mildly symptomatic patients with chemotherapy-naïve mCRPC (N=1088). The median follow-up was 49.2 months. Hematologic events were not reported among the AEs in this study.^3,4
• LATITUDE was a phase 3, randomized, double-blind, placebo-controlled study of ZYTIGA plus prednisone with androgen deprivation therapy (ADT) versus placebo with ADT in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (mCSPC). At the final analysis, at a median follow-up of 51.8 months, grade 3 and 4 hematological AEs were evaluated.^5,6

CLINICAL DATA

COU-AA-301 Study

de Bono et al (2011)¹ evaluated the efficacy and safety of ZYTIGA plus prednisone compared to placebo plus prednisone in patients with mCRPC whose disease had progressed after docetaxel-based chemotherapy (N=1195).

Study Design/Methods

• Phase 3, randomized, double-blind, placebo-controlled, multinational study.
• Patients were randomized 2:1 to receive the following:
  • ZYTIGA 1,000 mg orally (PO) once daily and prednisone 5 mg PO twice daily (n=797) or placebo and prednisone 5 mg PO twice daily (n=398).
  • ADT, a gonadotropin-releasing hormone (GnRH) analog, or prior orchiectomy was required in both arms.⁷
• Study treatment continued until disease progression documented as based on prostate-specific antigen (PSA) concentration, radiographic imaging, and clinical findings.
• Selected inclusion criteria: patients who met hematologic and chemistry laboratory criteria, including serum albumin level ≥ 3.0 g/dL, hemoglobin ≥ 9.0 g/dL independent of transfusion, platelet count ≥ 100,000/μL, serum creatinine < 1.5 x ULN, and serum potassium ≥ 3.5 mmol/L were included in the study.⁷

Results

Key Safety Outcomes - Hematological Events

• The median follow-up was 12.8 months at the time of the interim analysis.¹
• Fizazi et al (2012)² reported the final efficacy and safety analysis of COU-AA-301 study at a median follow up was 20.2 months.
• The rates of grade 3 and 4 AEs in both treatment groups revealed results consistent with those of the first interim analysis, as summarized in Table: Hematological AEs - Final Analysis.²

COU-AA-302 Study

Ryan et al (2013 and 2015)^3,4 evaluated the efficacy and safety of ZYTIGA plus prednisone compared to placebo plus prednisone in asymptomatic or mildly symptomatic patients with chemotherapy-naïve mCRPC (N=1088).

Study Design/Methods

• Phase 3, randomized, double-blind, placebo-controlled, multinational study.
• Patients were randomized to receive:
  • ZYTIGA 1000 mg PO once daily and prednisone 5 mg PO twice daily (n=546) or placebo and prednisone 5 mg PO twice daily (n=542).
  • ADT, GnRH analog, or prior orchiectomy was required in both arms.⁸
• Treatment continued until radiographic or clinical (cytotoxic chemotherapy, radiation or surgical treatment for cancer, pain requiring chronic opioids, or Eastern Cooperative Oncology Group performance status (ECOG PS) decline to 3 or more) disease progression, unacceptable toxicity, or withdrawal. Patients were allowed to continue blinded study medication after radiographic progressive disease in absence of unequivocal clinical progressive disease.⁸
• Select inclusion criteria: patients who met specific hematologic and chemistry laboratory parameters, including hemoglobin ≥ 10.0 g/dL independent of transfusion, platelet count ≥ 100,000/µL, and serum albumin ≥ 3.5 g/dL were included in the study⁸

Results

• Ryan et al (2015)⁴ reported the final efficacy and safety analysis of the COU-AA-302 study at a median follow-up of 49.2 months.
• Hematologic events were not reported among the AEs in this study.

LATITUDE Study

Fizazi et al (2017 and 2019)^5,6 evaluated the efficacy and safety of ZYTIGA plus prednisone with ADT vs placebos with ADT for the treatment of newly diagnosed, high-risk mCSPC (N=1199).

Study Design/Methods

• Phase 3, randomized, double-blind, placebo-controlled, multinational, multicenter study.
• Patients were randomized 1:1 to receive either ZYTIGA 1,000 mg plus prednisone 5 mg PO daily with ADT (n=597) or placebo PO daily with ADT (n=602).
  • Patients were stratified by ECOG PS grade (0 or 1 vs 2) and by presence or absence of visceral disease.
  • Patients who had not had surgical castration received ongoing ADT to reach or maintain a serum testosterone level <50 ng/dL.
• Selected inclusion criteria: patients with adequate hematological functions including hemoglobin ≥ 9.0 g/dL (independent of transfusion), neutrophils ≥ 1.5 × 10⁹/L, and platelets ≥ 100 × 10⁹/L were included in the study.⁹

Results

Key Safety Outcomes - Hematological Events

• At the time of the final analysis, median follow-up was 51.8 months.⁶
• The rates of grade 3 and 4 hematological AEs in both treatment groups are summarized in Table: Hematological AEs in Any Group.

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 was conducted on 18 June 2025.