A phase II study (AARDVARC) of AZD4635 in combination with durvalumab and cabazitaxel in patients with progressive, metastatic, castration-resistant prostate cancer

Abstract

Background: This phase II nonrandomized study evaluated the efficacy and safety of AZD4635 in combination with durvalumab (Arm A) or durvalumab plus cabazitaxel (Arm B) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel and ≥1 novel hormonal agent.

Patients and methods: The primary endpoint was radiographic progression-free survival (rPFS) per RECIST v1.1 (soft tissue) or the Prostate Cancer Clinical Trials Working Group 3 (bone). Secondary endpoints included safety, tolerability, overall survival, confirmed prostate-specific antigen (PSA₅₀) response, pharmacokinetics, and objective response rate. Enrollment in Arm A was stopped following a sponsor decision unrelated to safety. The study was stopped based on the planned futility analysis due to low PSA₅₀ response in Arm B.

Results: In the final analysis (1 November 2021), 30 patients were treated (Arm A, n = 2; Arm B, n = 28). The median rPFS in Arm B was 5.8 months (95% confidence interval 4.2-not calculable). Median rPFS was 5.8 months versus 4.2 months for patients with high versus low blood-based adenosine signature. The most common treatment-related adverse events in Arm B were nausea (50.0%), diarrhea (46.4%), anemia and neutropenia (both 35.7%), asthenia (32.1%), and vomiting (28.6%). Overall, AZD4635 in combination with durvalumab or AZD4635 in combination with cabazitaxel and durvalumab showed limited efficacy in patients with mCRPC.

Conclusions: Although the safety profile of both combinations was consistent with known safety data of the individual agents, the results of this trial do not support further development of the combinations.

Keywords: AZD4635; cabazitaxel; durvalumab; metastatic castration-resistant prostate cancer; pharmacokinetics; safety.

Figure 1

Radiographic PFS in Arm B (assessable-for-efficacy-analysis set). For the Kaplan–Meier plot, patients who did not progress at the time of analysis were censored at their last evaluable RECIST v1.1 assessment or bone scan. If the patient had disease progression or died after two or more missed radiologic visits, the patient was censored at the time of the latest evaluable RECIST v1.1 or bone scan assessment before the two missed visits. PFS, progression-free survival; RECIST v1.1, Response Evaluation Criteria In Solid Tumors version 1.1.

Figure 2

PSA response, best percentage change from baseline for Arm B (PSA-assessable analysis set). The −50% reference line represents 50% reduction of PSA in best percentage change from baseline. PSA₅₀ response was defined as the proportion of patients achieving a ≥50% decrease in PSA from baseline to the lowest post-baseline PSA, confirmed by a consecutive PSA ≥3 weeks later. If there was a PSA decline from baseline, progression was defined as the date of the first PSA increase (i.e. both ≥25% and ≥2 ng/ml above the nadir) and was confirmed by a second value ≥3 weeks later, even if within 12 weeks. If there was no PSA decline from baseline, progression was defined as a ≥25% increase and a ≥2 ng/ml increase from baseline beyond 12 weeks. Best percentage change from baseline in PSA is the maximum percentage reduction from baseline or the minimum percentage increase from baseline in the absence of a reduction. PSA, prostate-specific antigen; PSA₅₀, proportion of patients achieving a ≥ 50% decrease in PSA from baseline to the lowest post-baseline PSA; QD, once daily; Q3W, every 3 weeks.

Figure 3

Radiographic PFS in Arm B by adenosine-signaling signature high versus low level (assessable-for-efficacy-analysis set). 1 Patient did not have adenosine data. CI, confidence interval; HR, hazard ratio; NC, not calculable; PFS, progression-free survival.