ZYTIGA - IMAAGEN Study

Summary

• IMAAGEN (IMpact of Abiraterone Acetate in Prostate-Specific AntiGEN) is a phase 2, multicenter, single-arm, open-label study of ZYTIGA plus daily prednisone for the treatment of high-risk, non-metastatic castration-resistant prostate cancer (nmCRPC) in 131 patients with rising prostate-specific antigen (PSA) and castrate levels of serum testosterone. PSA was significantly reduced, with 86.9% achieving a 50% reduction in PSA during cycles 1-6 (PSA50; P<0.0001) and 59.8% achieving a 90% reduction in PSA (PSA90). Median time to PSA progression (TTPP) was 28.7 months (95% CI, 21.2-38.2 months). Median time to radiographic evidence of disease progression was not reached but was estimated to be 41.4 months (95% CI, 27.6 months-not estimable) by sensitivity analysis (n=15). Adverse events (AEs), grade ≥3 AEs, and serious AEs (SAEs) were reported in 96.2%, 61.1%, and 43.5% of patients, respectively. The most common AEs were hypertension, fatigue, and hypokalemia reported in 42.0%, 39.4%, and 33.6% of patients, respectively.¹

CLINICAL DATA

IMAAGEN Study

Ryan et al (2018)¹ evaluated the safety and efficacy of ZYTIGA plus prednisone for the treatment of nmCRPC in patients with rising PSA levels despite castrate levels of testosterone (N=131).

Study Design/Methods

• Phase 2, multicenter, single-arm, open-label, proof-of-concept study (NCT01314118)
• Patients were enrolled from April 2011 to July 2013.
• Patients received ZYTIGA 1,000 mg plus prednisone 5 mg orally daily.
  • Enrolled patients continued androgen deprivation therapy (ADT) or had orchiectomy.
  • Study treatment continued until radiographic evidence of metastatic disease progression, withdrawal of consent, or intolerable toxicity.
• PSA assessments were conducted at baseline, after cycles 3 and 6, and every 2 cycles thereafter. Imaging studies were conducted at baseline, after cycles 3 and 6, and every 3 cycles thereafter.
• The study included patients with confirmed nmCRPC and serum testosterone levels
  <50 ng/dL, a rising PSA level defined as either absolute PSA ≥10 ng/mL at screening, or a PSA doubling time (PSADT) of ≤10 months.
• After meeting all other entry criteria, patients underwent technetium bone scan as well as either computed tomography (CT) or magnetic resonance imaging (MRI) scan to confirm non-metastatic status.
• Select exclusion criteria: prior or current evidence of local disease progression or metastatic disease per modified Response Evaluation Criteria in Solid Tumors (RECIST); prior chemotherapy for CRPC; prior aminoglutethimide or ketoconazole for the treatment of prostate cancer; or current antiandrogen therapy
• Primary endpoint: proportion of patients with ≥50% reduction in PSA levels during cycles 1-6 of treatment (1 cycle=28 days)
• Secondary endpoints:
  • TTPP defined as the time between initiation of ZYTIGA plus prednisone and the time that a ≥25% increase and an absolute increase of ≥2 ng/mL from the nadir is documented, which is confirmed by a second value obtained after ≥3 weeks
  • Time to radiographic evidence of disease progression
  • Proportion of patients achieving a ≥30% (PSA30), PSA50, or PSA90 reduction in PSA by the end of cycle 6
  • Changes in PSA levels from baseline and over time, and testosterone levels from baseline and after cycles 3 and 6
  • Safety

Results

Patient Characteristics

• Median age: 72 years (range, 48-90 years)
• 85.5% of patients had a performance status of 0; 82.4% of patients were White and 14.5% of patients were Black.
• Median Gleason score (n=125) at baseline: 7 (range, 4-10)
• Mean testosterone level at baseline (n=116): 10.308 ng/dL
• Median PSA level at screening: 11.9 ng/mL (range, 1.3-167.8 ng/mL)
• Median PSADT among 52 patients with PSA <10 ng/mL: 3.4 months (range, 1.19.4 months)

Efficacy

• The median treatment duration was 22.14 months (range, 0.152 months), the median number of study treatment cycles initiated was 25 (range, 1-57 cycles), and estimated median follow-up in the study was 40 months.
• There were 122 patients evaluable for PSA response during the core treatment phase.
• During cycles 1-6, 86.9% of patients achieved ≥50% reduction in PSA levels (95% CI, 80.9%-92.9%; P<0.0001).
  • Patients achieving a ≥30% reduction in PSA levels: n=111 (91%)
  • Patients achieving a ≥90% reduction in PSA levels: n=73 (59.8%)
• PSA levels that were considered undetectable (<0.2 ng/mL) were achieved in
  27 patients (22.1%), and 7 patients (5.7%) had PSA levels that were <0.02 ng/mL.
• Testosterone levels were reduced by approximately 96% by the end of cycle 3 and remained so by the end of cycle 6.
• The median TTPP was 28.7 months (95% CI, 21.2-38.2 months).
• At the time of this analysis, 31 patients (23.7%) had radiographic evidence of disease progression as reported by investigators.
  • The remaining 100 patients (76.3%) were censored, having discontinued treatment prior to disease progression, or were continuing the study without confirmed progression. At 48 months, 62% of patients were estimated to be progression free.
  • The median time to radiographic disease progression was not reached; however, a sensitivity analysis of 15 patients with unconfirmed progression that led to study discontinuation showed the median time to radiographic progression was estimated to be 41.4 months (95% CI, 27.6 months-not estimable).
• Post hoc analyses
  • Patients with baseline testosterone ≥12.5 ng/dL (n=29) experienced significantly longer TTPP (P=0.03) and a nonsignificant increase in radiographic evidence of disease progression (P=0.12) as compared with patients with baseline testosterone <12.5 ng/dL (n=94).
  • Analyses after 3 cycles of therapy grouped patients into ranges of PSA reduction (<50% [n=17]; 50%-<90% [n=46]) and demonstrated that a greater reduction in PSA was associated with prolonged TTPP (median 15.7, 21.3, and 38.2 months, respectively [P=0.003]) and prolonged time to radiographic evidence of disease progression (median 14.8 months, 24.8 months, and not reached, respectively [P=0.002]).
  • While Black patients (n=19) had higher baseline PSA levels compared to other races (median 27.8 ng/mL), TTPP and time to radiographic evidence of disease progression were similar.
  • In a biomarker study in 30 long-term responders, no AR-V7, KLK2, KLK3, PITX2, and TMP.ERG expression was detected. In these patients, expression of genes crucial for T cell effector function and anti-tumor immune response (ie, GZMB, GZMK, PRF1, and CD3e) were expressed at high levels as demonstrated via microarray analysis. Pro-inflammatory cytokine expression, such as IFNgamma and IL-6, and expression of known checkpoint molecules, such as LAG-3 and PD-1, was low.² 

Safety

• All patients were evaluable for safety. AEs were assessed using National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03.
• 96.2% of patients reported AEs, of which 90.1% were drug related.
• 15.3% of patients had AEs which led to study treatment discontinuation.
  • No patient discontinued ZYTIGA plus prednisone due to mineralocorticoid excess or required prednisone dose escalation for management.
• 43.5% of patients had an SAE, of which 22.1% were drug related.
  • Grade 5 AEs were reported in 5 patients (4%), and 2 additional deaths due to grade 4 injury (motorcycle accident) and grade 3 pneumonia were recorded. Six patients had a single SAE (injury, pneumonia, aspiration pneumonia, myocardial infarction, congestive cardiac failure, and coronary artery disease). One patient had sepsis, pneumonia, and acute respiratory failure.
  • The most common AEs are summarized in Table: Common Adverse Events Reported in ≥15% of Patients.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 21 January 2025.