ARX517 Demonstrates Early Efficacy With Favorable Safety in Heavily Pretreated mCRPC

John Shen, MD

The prostate-specific membrane antigen (PSMA)­–targeted antibody-drug conjugate (ADC) ARX517 displayed preliminary efficacy and a strong safety profile in patients with metastatic castration-resistant prostate cancer (mCRPC), according to findings from the phase 1/2 APEX-01 study (NCT04662580) presented in a poster during the 2023 ESMO Congress.¹

Patients who received the ADC experienced deep PSA reductions with increasing doses of the agent; 61%, 52%, and 26% of those in cohorts 6 to 8 (n = 23) achieved reductions of at least 30% (PSA30), 50% (PSA50), and 90% (PSA90), respectively. Additionally, a reduction of at least 50% in circulating tumor DNA (ctDNA) was reported in 81% of evaluable patients in cohorts 6 to 8 (n = 21). In cohorts 4 to 8, target lesion reduction by RECIST v1.1 criteria was observed in 5 of 9 evaluable patients; 2 of these patients achieved confirmed responses.

No dose-limiting toxicities (DLTs) or treatment-related serious adverse events (SAEs) were reported at any dose up to 2.88 mg/kg every 3 weeks. No grade 4 or 5 treatment-related adverse events (TRAEs) were observed.

“Without PSMA imaging selection, ARX517 monotherapy achieved favorable safety and demonstrated early efficacy, with deep PSA and ctDNA reductions and confirmed RECIST v1.1 tumor response in patients with mCRPC who progressed on multiple FDA-approved treatments,” John Shen, MD, medical oncologist in the Medical Oncology Department at Jonsson Comprehensive Cancer Center of UCLA, in Los Angeles, California, and colleagues, wrote in the poster.

ARX517 is a novel ADC that consists of a fully humanized anti-PSMA monoclonal antibody conjugated to the potent microtubule inhibitor amberstatin-269. The agent is specifically designed to reduce off-target ADC instability-related toxicity that has been reported in earlier-generation anti-PSMA ADCs. In July 2023, the FDA granted fast track designation to ARX517 for the treatment of patients with mCRPC following progression on an AR pathway inhibitor.²

The first-in-human APEX-01 study enrolled patients with mCRPC who experienced progression after receiving at least 2 FDA-approved therapies, 1 of which being a second-generation AR pathway inhibitor. Progression was documented as experiencing 1 or more of the following: progressive disease (PD) by RECIST v1.1 criteria, PSA progression, and/or radiographic progression in bone.

The primary objectives of the trial were to determine the safety and tolerability of the agent and to establish the maximum tolerated and recommended phase 2 doses.¹

The phase 1a dose-escalation portion of the research was conducted utilizing a 3 +3 design. Here, patients received ARX517 at escalating doses every 3 weeks and were divided into 8 cohorts: cohort 1 (n = 1; 0.32 mg/kg), cohort 2 (n = 4; 0.64 mg/kg), cohort 3 (n = 3; 1.07 mg/kg), cohort 4 (n = 21; 1.4 mg/kg), cohort 5 (n = 5; 1.7 mg/kg), cohort 6 (n = 20; 2.0 mg/kg), cohort 7 (n = 6; 2.4 mg/kg), and cohort 8 (n = 8; 2.88 mg/kg). The phase 1b dose-expansion portion will enroll approximately 20 to 30 patients per cohort.

At baseline, the median patient age in the total population was 68.0 years (range, 50-100), and the median weight was 86.7 kg (range, 54-133). Most patients were White (82%), 59% had an ECOG performance status of 1, 34% had measurable lesions by RECIST v1.1 criteria, and 80% had a bone lesion site. The median PSA was 47.0 ug/L (range, 1-3845), the median alkaline phosphatase was 108.0 U/L (range, 30-848), and the median lactate dehydrogenase level was 200.0 U/L (range, 93-1492).

Moreover, the median number of prior lines of therapy received was 4.0 (range, 1-13). Sixty-six percent of patients had previously received a taxane, 46% had received immunotherapy, and 17% had received PSMA treatment. The median number of prior AR pathway inhibitor treatments was 2.0 (range, 1-5). Previous AR inhibitors consisted of abiraterone (Zytiga; 75%), enzalutamide (Xtandi; 69%), both abiraterone and enzalutamide (48%).

The data cutoff date was September 5, 2023. Additional findings in efficacy-evaluable patients showed that of those treated in cohorts 1 to 3 (n = 7), 29% achieved PSA30; no patients in these cohorts experienced PSA50 or PSA90. Of those in cohort 4 (n = 16), 38%, 25%, and 6% of patients achieved PSA30, PSA50, and PSA90, respectively. Of those in cohort 5 (n = 5), 40% achieved PSA30 % and no patients experienced PSA50 or PSA90.

Regarding safety, grade 1/2 AEs were present in 67%, 100%, 57%, 100%, 75%, 100%, and 83% of patients in cohorts 2 through 8, respectively, with an overall rate of 74% in all cohorts. Grade 3 TRAEs occurred in cohort 4 (5%), cohort 5 (20%), cohort 6 (10%), cohort 7 (17%), and cohort 8 (17%), for an overall rate of 9%. There were no grade 4 or grade 5 TRAEs. One patient in both cohort 2 and 6 experienced AEs that led to discontinuation of treatment. Patients in cohort 1 did not experience AEs of any kind.

Grade 3 TRAEs across all cohorts included decreased lymphocyte count (5%), decreased platelet count (3%), and left ventricular dysfunction (2%). The most common grade 1/2 TRAEs reported across cohorts included dry mouth (28%), dry eye (22%), fatigue (20%), diarrhea (15%), decreased appetite (14%), nausea (14%), dysgeusia (12%), vomiting (12%), and increased aspartate aminotransferase (11%).

References

1. Shen J, Pachynski R, Nordquist LT, et al. APEX-01: First-in-human phase I/II study of ARX517 an anti- prostate-specific membrane antigen (PSMA) antibody-drug conjugate (ADC) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Ann Oncol. 2023;34(suppl 2):S974-S975. doi:10.1016/j.annonc.2023.09.2752
2. FDA grants Fast Track Designation for Ambrx’s ARX517 for the treatment of metastatic castration-resistant prostate cancer. News release. Ambrx Biopharma Inc. July 19, 2023. Accessed October 25, 2023. https://ir.ambrx.com/news/news-details/2023/FDA-Grants-Fast-Track-Designation-for-Ambrxs-ARX517-for-the-Treatment-of-Metastatic-Castration-Resistant-Prostate-Cancer/default.aspx