A phase 2 study published on March 2, 2024 in Cancer Immunology, Immunotherapy evaluated the efficacy and safety of the adenosine 2A receptor (A2AR) antagonist AZD4635 in combination with either durvalumab or oleclumab for patients with metastatic castration-resistant prostate cancer (mCRPC). The open-label, randomized study was conducted at 9 centers in the United States and was funded by AstraZeneca.
The purpose of the study was to assess whether inhibition of the A2AR with AZD4635, in combination with immune-targeting drugs, could provide clinical benefit for patients with mCRPC who had limited remaining treatment options. Preclinical evidence suggests that A2AR inhibition may reduce the immunosuppressive effects of adenosine in the tumor microenvironment and potentially enhance anti-tumor immune responses when combined with other immunotherapies.
The study enrolled 59 patients with histologically or cytologically confirmed mCRPC who had previously received and progressed on at least 2 lines of approved systemic therapy for mCRPC within 6 months of enrollment, including a second-generation hormonal agent such as abiraterone, enzalutamide, or apalutamide. Patients were randomized to one of two treatment modules:
- Module 1 (n=29): AZD4635 75 mg orally once daily + durvalumab 1500 mg intravenously every 4 weeks
- Module 2 (n=30): AZD4635 50 mg (first 25 patients) or 75 mg orally once daily + oleclumab 1500 mg intravenously every 2 weeks for 4 doses, then every 4 weeks
The study population was heavily pretreated, with a median of 4 prior systemic therapies (range 1-9). The median age was 72 years (range 53-90) and most patients were white (80%). At baseline, 41% of patients had more than 2 metastatic sites, with bone (85%), distant lymph nodes (42%), and local/regional lymph nodes (42%) being the most common sites of metastasis.
The primary endpoints were objective response rate (ORR) per RECIST v1.1 and prostate-specific antigen (PSA) response rate. Secondary endpoints included radiological progression-free survival (rPFS), overall survival (OS), safety, and pharmacokinetics.
Results showed limited anti-tumor activity with the AZD4635 combination regimens in this refractory mCRPC population:
- ORR: 1 confirmed complete response in Module 1; no objective responses in Module 2
- PSA response rate: 2 confirmed PSA responses (1 in each module)
- Median rPFS: 2.3 months (95% CI: 1.6-3.8) in Module 1; 1.5 months (95% CI: 1.3-4.0) in Module 2
- Median OS: 10.7 months (95% CI: 7.2-NE) in Module 1; not reached in Module 2
The safety profile was generally manageable, with no new safety signals identified. The most common adverse events possibly related to AZD4635 were:
No dose-limiting toxicities or treatment-related serious adverse events were observed. Three patients (10.3%) in Module 1 and 2 patients (6.7%) in Module 2 reported at least one grade ≥3 adverse event possibly related to AZD4635. One patient in each module discontinued AZD4635 due to a treatment-related adverse event.
Pharmacokinetic analysis showed that AZD4635 exposures were similar between the two modules, with a geometric mean trough concentration of 124.9 ng/mL in Module 1.
An exploratory analysis examined progression-free survival based on a blood-based adenosine gene expression signature. Contrary to previous findings in a phase 1 study, there was no apparent difference in median PFS between patients with high versus low adenosine signature scores (1.7 vs 2.3 months, respectively).
The study had several limitations, including the small sample size inherent to phase 2 trials, which precluded statistical comparisons between the treatment modules. Additionally, the follow-up period was relatively short, limiting long-term safety assessments.
The authors concluded that AZD4635 in combination with durvalumab or oleclumab demonstrated minimal anti-tumor activity in this heavily pretreated mCRPC population, despite having a manageable safety profile. They noted that these results are consistent with the limited efficacy observed with other checkpoint inhibitors in refractory prostate cancer.
The potential clinical impact of this study is likely to be limited given the lack of meaningful efficacy signals. However, the results provide important insights into the challenges of utilizing immunotherapy approaches in mCRPC, which is generally considered an immunologically "cold" tumor type with low T cell infiltration. The study highlights the need for continued research into novel therapeutic strategies that can overcome the immunosuppressive tumor microenvironment in prostate cancer.
This trial adds to the growing body of evidence suggesting that single-agent checkpoint inhibition or adenosine pathway blockade may be insufficient to generate robust anti-tumor responses in mCRPC. Future research directions may focus on combination approaches that target multiple immune evasion mechanisms simultaneously or on identifying biomarkers that can better predict which patients are most likely to benefit from immunotherapy.
It is worth noting that another ongoing phase 2 study (NCT04495179) is investigating AZD4635 in combination with durvalumab and cabazitaxel in mCRPC patients. The results of that trial may provide additional insights into whether the addition of chemotherapy to this immunotherapy combination could improve outcomes.
In the broader context of mCRPC treatment, these findings underscore the continued unmet need for effective therapies in patients who have progressed on standard treatments like taxanes and novel hormonal agents. While recent advancements such as PSMA-targeted radioligand therapy (e.g., 177Lu-PSMA-617) have shown promise in select patients, there remains a critical need for additional treatment options in this setting.
For clinicians treating patients with mCRPC, this study suggests that the combination of AZD4635 with durvalumab or oleclumab is unlikely to provide significant clinical benefit in heavily pretreated patients. However, the manageable safety profile observed may support further investigation of these agents in other combinations or earlier disease settings.
The negative results of this trial also highlight the importance of continued basic and translational research to better understand the immune landscape of prostate cancer and identify novel targets for therapeutic intervention. As our understanding of tumor immunology evolves, new strategies may emerge to effectively harness the immune system against this challenging malignancy.
In conclusion, while this phase 2 study did not demonstrate meaningful clinical activity for AZD4635-based combinations in refractory mCRPC, it provides valuable data to inform future research directions in the field of prostate cancer immunotherapy. The ongoing search for effective treatments in this patient population remains an important area of investigation in genitourinary oncology.
References
Falchook GS, Reeves J, Gandhi S, et al. A phase 2 study of AZD4635 in combination with durvalumab or oleclumab in patients with metastatic castration-resistant prostate cancer. Cancer Immunol Immunother. 2024;73(4):72. Published 2024 Mar 2. doi:10.1007/s00262-024-03640-6
