FDA Awards Fast Track Designation to ARX517 for Metastatic Castration-Resistant Prostate Cancer

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The FDA has granted fast track designation to ARX517 for use as a potential treatment option in patients with metastatic castration-resistant prostate cancer who experience disease progression on an androgen receptor pathway inhibitor.

The FDA has granted fast track designation to ARX517 for use as a potential treatment option in patients with metastatic castration-resistant prostate cancer (mCRPC) who experience disease progression on an androgen receptor (AR) pathway inhibitor.¹

An antibody-drug conjugate (ADC), ARX517 is comprised of a fully humanized anti–prostate-specific membrane antigen (PSMA) monoclonal antibody that is linked to AS269. After the product binds to PSMA on the surface of cancer cells, the drug is internalized and its payload, referred to as pAF-AS269, is released after lysosomal metabolism. Notably, the agent is noted to display a homogenous drug-to-antibody ratio, as well as biophysical properties that are comparable to monoclonal antibodies. With these features, ARX517 is hypothesized to be able to encourage specific cancer cell killing with fewer off-target adverse effects.

ARX517 is under exploration in patients with mCRPC as part of the ongoing phase 1/2 APEX-01 trial (NCT04662580).² Initial data from the trial, reported in February 2023, showed that when the ADC was given at dose levels starting at 0.32 mg/kg, it resulted in a reduction of prostate-specific antigen (PSA) that was greater than 30% in cohorts 2 to 5.³

All patients in cohort 6 (n = 3), who received ARX517 at 2.0 mg/kg, experienced reductions in PSA levels that was upward of 50%, with 2 patients experiencing a reduction of greater than 90%. Additionally, 1 of these 3 patients who had soft tissue measurable disease was found to achieve a partial response to treatment by RECIST v1.1 criteria at the time of their first scan.

At the time of the data release, 3 patients in cohort 7 had received the ADC, and no dose-limiting toxicities were observed.

“Receiving fast track designation from the FDA reinforces Ambrx’s belief in ARX517 as a potential novel treatment for mCRPC and underscores the urgent need for improved treatment options for patients at this advanced stage of prostate cancer,” Sandra Aung, PhD, chief clinical officer of Ambrx Biopharma, Inc., stated in a press release.¹

The open-label, dose-escalation and -expansion trial is enrolling patients with mCRPC whose tumors have progressed on 2 or more FDA-approved treatments for metastatic disease, including 1 AR receptor signaling inhibitor.^1,2 Specifically, they need to meet 1 of the following criteria: PSA progression defined as at least 2 rising PSA values, radiographic progression by RECIST v1.1 criteria, or progressive disease per the presence of new bone lesions. Patients also need to be at least 18 years of age and have acceptable blood counts.²

If they had central nervous system metastases, a history of invasive malignancies beyond the primary disease within the 2 years before study enrollment, marked QT prolongation at baseline, a history of interstitial lung disease or pneumonitis, or significant ocular issues, they will be excluded.

In phase 1 portion of the research, investigators examined escalating doses of ARX517, given every 3 weeks.³ Primary end points included safety, tolerability, and pharmacokinetics, and decline in PSA from baseline and/or tumor shrinkage represents an important secondary end point. A reduction in PSA levels of at least 50% had been correlated with improved survival in this population.

At the time of data release, 22 patients had received treatment with the agent spanning 7 dosing cohorts, comprised of a minimum of 3 patients each. Doses in these cohorts ranged from 0.32 mg/kg to 2.4 mg/kg.

Regarding safety, no serious toxicities were observed with the ADC, nor were any grade 3 or higher treatment-related toxicities reported. The maximum tolerated dose had not yet been reached.

Moreover, preclinical data presented at the 2023 AACR Annual Meeting showed that ARX517 had antitumor activity in enzalutamide (Xtandi)-sensitive and -resistant models of the disease.⁴ In the enzalutamide-sensitive mouse model, the ADC had activity; when given at a dose of 3 mg/kg in combination with enzalutamide at 10 mg/kg, it resulted in a tumor reduction of 86%. In a model that was resistant to enzalutamide, the administration of ARX517 at weekly doses of 3 mg/kg for 3 weeks hindered tumor growth by 79%.