AZD4635 Plus Durvalumab or Oleclumab Has Minimal Clinical Activity in mCRPC

The addition of AZD4635 to durvalumab (Imfinzi) or oleclumab did not elicit significant responses in heavily pretreated patients with metastatic castration-resistant prostate cancer (mCRPC), according to data from a phase 2 trial (NCT04089553) presented at the 2022 ESMO Congress.

Despite both combinations demonstrating a manageable safety profile, only 1 objective response was achieved in a patient treated with AZD4635 plus durvalumab. No responses were achieved in those who received the combination of AZD4635 and oleclumab.

“In this heavily pretreated population, AZD4635 with durvalumab or oleclumab demonstrated minimal antitumor activity,” lead study author Emerson Lim, MD, of Herbert Irving Comprehensive Cancer Center at NewYork-Presbyterian/Columbia University Irving Medical Center, wrote in a poster presentation of the data. “Exploring alternate dosing in less heavily treated patients may be beneficial.”

Patients with mCRPC who progress following treatment with taxane-based therapy or novel hormonal agents, such as enzalutamide (Xtandi), abiraterone acetate (Zytiga), or apalutamide (Erleada), have limited therapeutic options.

Inhibition of the adenosine 2A receptor (A2AR) reduces the immunosuppressive effects of adenosine and could complement immune-targeting agents like durvalumab. Previous data from a phase 1 trial (NCT02740985) showed that the A2AR antagonist, AZD4635, generated objective tumor and prostate-specific antigen (PSA) responses when administered as a monotherapy and in combination with durvalumab in patients with mCRPC.

The phase 2 trial aimed to further investigate AZD4635 in combination with durvalumab or oleclumab in this population. Specifically, the study enrolled patients with histologically or cytologically confirmed mCRPC who were naïve to immunotherapy. Patients were required to have a measurable lesion per RECIST v1.1 criteria and to have received at least 2 lines of prior therapy that included novel hormonal agents.

Upon enrollment, participants were randomly assigned into 2 groups: module 1 (n = 29) and module 2 (n = 30). Those in module 1 received 75 mg of oral AZD4635 given once daily in combination with 1500 mg of intravenous (IV) durvalumab given once every 4 weeks. The first 25 patients in module 2 received AZD4635 at 50 mg once daily, and the last 5 patients received AZD4635 at 75 mg once daily. All patients in module 2 also received 1500 mg of IV oleclumab given once every 2 weeks for 4 doses, and once every 4 weeks thereafter.

The primary end points of the trial were overall response rate (ORR) by RECIST v1.1 criteria and PSA-confirmed response. Secondary end points included radiologic progression-free survival (rPFS) at 6 months, overall survival (OS), duration of response, safety, pharmacokinetics, and antidrug antibodies.

In module 1, the median age was 73 years (range, 59-90), and 79.3% of patients were White. Additionally, 24.1% of patients had an ECOG performance status of 0 and 75.9% had a status of 1. The median number of prior systemic therapies received was 4 (range, 1-9); 3.4% of patients had received 1 prior line of therapy, 3.4% received 2 prior lines, 10.3% received 3 prior lines, 34.5% had 4 prior lines, 24.1% had 5 prior lines, 17.2% had 6 prior lines, and 6.9% received more than 6 prior lines.

In module 2, the median age was 72 years (range, 53-86) and 80.0% of patients were White. In this group, 23.3% of patients had an ECOG performance status of 0 and 73.3% had a status of 1. The median number of lines of prior systemic therapies received was 4 (range, 2-8); 13.3%, 30.0%, 20.0%, 20.0%, 6.7%, and 10.0% of patients received 2, 3, 4, 5, 6, or more than 6 prior systemic therapies, respectively.

The mean total treatment duration for AZD4635 was 3 months across both modules.

Additional data showed the median rPFS was 2.3 months (95% CI, 1.6-3.8) in module 1 and 1.5 months (95% CI, 1.3-4.0) in module 2. The median OS was 10.7 months (95% CI, 7.2–not evaluable [NE]) in module 1 and not yet reached (95% CI, 10.6 months-NE) in module 2.

Among all patients, those with low adenosine signaling signature achieved a median PFS of 13.9 weeks (95% CI, 6.7-17.6) compared with 9.9 weeks (95% CI, 5.6-13.6) in those with a high signature (HR, 1.5; 95% CI, 0.8-2.8).

Regarding safety, 82.8% of patients in module 1 and 83.3% of those in module 2 experienced at least 1 any-grade adverse effect (AE). The most frequent AEs possibly related to study treatment were nausea (37.9% and 53.3% in modules 1 and 2, respectively), fatigue (20.7% and 30%), decreased appetite (17.2% and 16.7%), and vomiting (10.3% and 23.3%) .

Additionally, 10.3% of patients in module 1 and 6.7% of patients in module 2 experienced at least 1 grade 3 or higher AE that was potentially related to AZD4635. One patient in module 2 experienced an AE related to AZD4635 that led to treatment discontinuation. Notably, no patients experienced serious AEs that were related to any of the study agents.

No dose-limiting toxicities were reported in 6 evaluable patients enrolled to module 2. However, 1 patient in this module had grade 5 cardiac arrest that was deemed to be unrelated to study treatment.

“There were no significant safety concerns that preclude further development of AZD4635 in combination with durvalumab or oleclumab,” the study authors concluded. “Exploring alternative dosing in less heavily treated patients may be beneficial.”

Reference

Lim E, Reeves J, Gandhi S, et al. Phase II study of AZD4635 in combination with durvalumab or oleclumab in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC). Ann Oncol. 2022;33(suppl 7):S1182-S1183. doi:10.1016/j.annonc.2022.07.1882