ZYTIGA - Use of ZYTIGA in Combination with Docetaxel for the Treatment of Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Summary

• A phase 2, randomized, 2-stage, open-label study of ZYTIGA 1,000 mg orally daily plus prednisone 5 mg twice daily (BID) in combination with docetaxel 75 mg/m² intravenously (IV) every three weeks (Q3W; arm A) vs docetaxel monotherapy plus prednisone (arm B) for the treatment of chemotherapy-naïve patients with metastatic castrationresistant prostate cancer (mCRPC) progressing after ZYTIGA plus prednisone therapy noted no statistically significant differences in efficacy outcomes (n=88). Median radiographic progression-free survival (rPFS), the primary study endpoint, was 11.4 months vs 10.5 months in arms A and B, respectively. The most common grade 3-4 toxicities in arms A and B, respectively, included: neutropenia (57% vs 29%; P=0.027), febrile neutropenia (17% vs 10%), diarrhea (9% vs 7%), and asthenia (11% vs 10%).^1,2
• A phase 1b, open-label, dose-escalation study evaluated the maximum safe dose combination of ZYTIGA plus prednisone and docetaxel in chemotherapynaïve patients with mCRPC (N=22). The recommended phase 2 dose was found to be docetaxel 75 mg/m² IV plus ZYTIGA 1,000 mg daily plus prednisone 10 mg daily. Dose-limiting toxicities (DLTs) observed with this dose combination included grade 3 hematuria and neutropenia with fever identified in one patient (who had preexisting hematuria) of the 6 included in this cohort. Efficacy outcomes were pooled (n=21). A decline from baseline in prostate-specific antigen (PSA) of ≥50% and ≥90% was observed for 85.7% and 66.7% of patients, respectively. At a median follow-up of 14.5 months, 8 patients had PSA progression and 6 had radiographic progression or died. Systemic exposure was comparable for docetaxel and ZYTIGA when given alone or in combination.³

CLINICAL Data

Phase 2 Study

Duran et al (2020)¹and Puente et al (2018)² evaluated the safety and efficacy of ZYTIGA plus prednisone in combination with docetaxel vs docetaxel plus prednisone for the treatment of chemotherapy-naïve patients with mCRPC progressing after ZYTIGA plus prednisone (N=148).

Study Design/Methods

• Phase 2, randomized, open-label, multicenter study in Spain (ABIDO-SOGUG trial; NCT02036060)
• Study consists of 2 stages:
  • Stage 1: patients received ZYTIGA 1,000 mg daily plus prednisone 5 mg BID until radiological or unequivocal clinical progression.²
  • Stage 2: upon progression, patients were randomized to receive docetaxel 75 mg/m² IV Q3W in combination with ZYTIGA 1,000 mg daily plus prednisone (arm A) or without ZYTIGA (arm B)
• Primary endpoint: rPFS
• Secondary endpoints: radiological response (RR), overall survival (OS), PSA response, PSA-PFS, and safety
• Inclusion criteria: chemotherapy-naïve mCRPC; no visceral metastases; Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1; serum testosterone <50 ng/dL; and adequate hematologic, hepatic, and renal function.²

Results

Patient Characteristics

• Stage 2 included 88 randomized patients (arm A, n=46 and arm B, n=42) who were evaluable for efficacy and safety.
• Median age was 69 years and ECOG PS was 0 in 43% of patients.
• Metastases included: bone (91%), liver (11%), and lung (5%).

Efficacy

• No statistically significant differences were noted in efficacy evaluations. Median rPFS was 11.4 months vs 10.5 months; and 12 month rPFS was 43% vs 45% in arms A and B, respectively.
• Median PSA-PFS was 6.2 months vs 5.5 months and median OS was 17.3 months vs 16.9 months in arms A and B, respectively.
• Twenty-four (52%) patients in arm A and 19 (46%) patients in arm B achieved a ≥50% PSA response.
• RR was achieved in 15% vs 7% of patients in arms A and B, respectively; and disease control rate was 74% in both arms.

Safety

• The median dose intensity for docetaxel was 86% and 90% for arms A and B, respectively, and 91% for ZYTIGA.
• Eleven patients discontinued treatment due to non-hematological toxicity (arm A, n=5 and arm B, n=6).
• The most common grade 3-4 toxicities in arms A and B, respectively, included: neutropenia (57% vs 29%; P=0.027), febrile neutropenia (17% vs 10%), diarrhea (9% vs 7%), and asthenia (11% vs 10%).

Phase 1b Study

Tagawa et al (2016)³ conducted a study to determine the safe dose combination of docetaxel and ZYTIGA plus prednisone in 3 cohorts of patients with chemotherapy-naïve mCRPC (N=22).

Study Design/Methods

• Phase 1b, open-label, dose-escalation study (COU-AA-206)
• Patients ≥18 years of age were eligible for enrollment if they had the following:
  • Histologically or cytologically confirmed prostate cancer
  • PSA progression according to Prostate Cancer Working Group 2 criteria or objective radiographic progression according to modified Response Evaluation Criteria in Solid Tumors (RECIST) or bone scans
  • ECOG PS ≤2
  • Adequate hematologic and biochemical indices
  • Medical or surgical castration (testosterone <50 ng/dL)
• Up to 4 cohorts could receive escalating doses of the combination therapy.
  • Cohort 1: docetaxel 60 mg/m² plus ZYTIGA 500 mg
  • Cohort 2: docetaxel 75 mg/m² plus ZYTIGA 500 mg
  • Cohort 3: docetaxel 75 mg/m² plus ZYTIGA 1,000 mg
  • Cohort 4 (if necessary): docetaxel 60 mg/m² plus ZYTIGA 1,000 mg
  • Docetaxel was administered every 3 weeks along with prednisone 5 mg orally twice daily; ZYTIGA was initiated 1 week following study initiation.
• Primary endpoint: proportion of patients with a DLT between weeks 2 and 7, defined as follows:
  • Nonhematologic toxicity ≥grade 3
  • Grade 4 neutropenia for greater than 7 days (or febrile neutropenia)
  • Grade 4 thrombocytopenia
  • Other intolerable toxicity
• Patients were permitted to discontinue docetaxel (due to toxicity or at investigator discretion) following DLT assessment and continue ZYTIGA plus prednisone until disease progression.
• The recommended phase 2 dose was the highest dose of ZYTIGA plus prednisone and docetaxel at which ≤2 of 6 patients experienced a DLT.
• Concentration-time data were used to estimate pharmacokinetic parameters.
• Secondary endpoints: best change from baseline in PSA; time to PSA progression; best overall response; objective response rate (ORR); time to rPFS; assessment of the effect of steady-state abiraterone acetate on docetaxel pharmacokinetics and vice versa

Results

Patient Characteristics

• Data have been published for cohorts 1 (n=7), 2 (n=8), and 3 (n=7). See Table: Baseline Characteristics for Patients in Cohorts 1, 2, and 3.
• During the first week, 2 patients were replaced due to docetaxel toxicity.

Safety

• The median duration of docetaxel treatment exposure was 8 cycles (range, 4-12), 9.5 cycles (range, 1-12), and 6.1 cycles (range, 1-9) for cohorts 1, 2, and 3, respectively.
• The median duration of ZYTIGA plus prednisone treatment exposure was 14.6 months (range, 7.8-23.2), 15.5 months (range, 3.0-19.1), and 4.7 months (range, 1.4-7.6) for cohorts 1, 2, and 3, respectively.
• At data cutoff, 12 patients (55%) remained on treatment.
• Of the 22 treated patients, 18 were evaluable for DLT assessment.
• DLTs observed included the following: syncope and hypertension in cohort 1; grade 4 neutropenia in 1 patient in cohort 2; and grade 3 hematuria during admission for elective cystolitholapaxy for preexisting hematuria with subsequent fever during neutropenia in 1 patient in cohort 3.
• The combination dose received by cohort 3 (docetaxel 75 mg/m² plus ZYTIGA 1,000 mg plus prednisone 10 mg) was found to be the recommended phase 2 dose, and, therefore, cohort 4 was not enrolled.
• Grade 3-4 adverse events (AEs) were reported in 21 (95.5%) of the 22 treated patients.
• Based on investigator assessment, of these 21 patients, all had AEs related to docetaxel, 11 (52.3%) had AEs related to ZYTIGA plus prednisone, and 18 (85.7%) had AEs related to prednisone.
• The most common grade 3-4 AEs included neutropenia (77.2%), leukopenia (45.5%), febrile neutropenia (31.8%), back pain (9.1%), and hypertension (9.1%).
• Of the 13 patients that experienced serious AEs, 11 had drug-related serious AEs (6 were related to ZYTIGA plus prednisone; 3 related to prednisone; and 10 related to docetaxel).

Efficacy

• In the pooled population of patients (from cohorts 1, 2, and 3) with postbaseline PSA data (n=21), 66.7% (n=14) of patients had ≥90% PSA decline from baseline and 85.7% (n=18) of patients had ≥50% PSA decline from baseline.
• With a median follow-up of 14.5 months and 8 (38.1%) PSA progression events, the median time to PSA progression was 22.87 months (95% CI: 7.95-22.87).
• Of the 10 patients with measurable disease at baseline, 6 had an objective tumor response based on RECIST (all were partial); 3 had stable disease; and 1 had progressive disease.
• Median rPFS was not reached.

Pharmacokinetics

• Systemic exposure to docetaxel, as assessed by mean maximum plasma concentration (C_max) and area under the curve from time 0 to infinity (AUC_∞), was comparable when administered alone or in combination with abiraterone acetate plus prednisone. C_max and AUC_∞ for abiraterone acetate were also comparable when abiraterone acetate plus prednisone was administered alone and in combination with docetaxel.

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 30 July 2025. Summarized in this response are relevant data from phase 1 and 2 studies of this doublet combination in men with mCRPC.