FDA grants Fast Track designation to ARX517 for metastatic castration-resistant prostate cancer

The FDA has granted accelerated 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 consists of a fully humanized prostate-specific membrane antigen (PSMA) monoclonal antibody that is bound to AS269. After the product binds to PSMA on the surface of cancer cells, the drug is internalized and its payload, named pAF-AS269, is released after lysosomal metabolism. In particular, the agent exhibits a homogeneous drug-antibody ratio as well as biophysical properties comparable to monoclonal antibodies. With these characteristics, ARX517 is hypothesized to be able to encourage the killing of specific tumor cells with fewer off-target adverse effects.

ARX517 is being explored in patients with mCRPC as part of the ongoing APEX-01 Phase 1/2 study (NCT04662580).2 Initial study data, reported in February 2023, showed that when ADC was administered at dose levels as low as 0.32 mg/kg, it resulted in a reduction in prostate specific antigen (PSA) of more 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 greater than 50%, with 2 patients experiencing greater than 90% reduction. In addition, 1 of these 3 patients with measurable soft tissue disease achieved a partial response to treatment according to RECIST v1.1 criteria at the time of the first scan.

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

Receiving expedited designation from FDA reinforces Ambrx’s belief in ARX517 as a potential new treatment for mCRPC and underscores urgent need for better treatment options for patients in this advanced stage of prostate cancer, Sandra Aung, PhD, Chief Clinical Officer of Ambrx Biopharma, Inc., said in a press release.1

The open-label, dose-escalation and -expansion study 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 In particular, they must meet 1 of the following criteria: PSA progression defined as at least 2 rising PSA values, radiographic progression according to RECIST v1.1 criteria, or progressive disease due to the presence of new bone lesions. Patients must also 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 2 years prior to study enrollment, marked prolongation of the QT interval at baseline, a history of interstitial lung disease or pneumonia, or significant eye problems will be excluded.

In Phase 1 of the research, the researchers looked at escalating doses of ARX517, given every 3 weeks.3 Primary endpoints included safety, tolerability, and pharmacokinetics, with PSA decline from baseline and/or tumor shrinkage being an important secondary endpoint. A reduction in PSA levels of at least 50% had been correlated with better survival in this population.

At the time of the data release, 22 patients had received treatment with the agent in 7 dosing cohorts, consisting 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 ADC, nor were any treatment-related toxicities of Grade 3 or higher reported. The maximum tolerated dose had not yet been reached.

Additionally, 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, ADC had activity; when given at a dose of 3 mg/kg in combination with enzalutamide at a dose of 10 mg/kg, it resulted in a tumor shrinkage of 86%. In an enzalutamide resistant model, administration of ARX517 at weekly doses of 3 mg/kg for 3 weeks impaired tumor growth by 79%.


  1. FDA grants accelerated designation for Ambrxs ARX517 for the treatment of metastatic castration-resistant prostate cancer. Press release. Ambrx Biopharma, Inc. July 19, 2023. Accessed July 19, 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
  2. ARX517 in subjects with metastatic castration-resistant prostate cancer (ARX517). ClinicalTrials.gov. Updated May 6, 2023. Accessed July 19, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04662580
  3. ARX517, Ambrx’s proprietary anti-PSMA ADC, shows encouraging data on single-agent safety and efficacy in patients with advanced prostate cancer. Press release. Ambrx Biopharma, Inc. February 16, 2023. Accessed July 19, 2023. https://ir.ambrx.com/news/news-details/2023/ARX517-Ambrxs-Proprietary-Anti-PSMA-ADC-Shows-Encouraging-Data- single-agent-on-safety-and-efficacy-in-patients-with-advanced-prostate-cancer/default.aspx
  4. Ambrx Presents New Preclinical Data on ARX517 and ARX305 at AACR 2023 Annual Meeting. Press Release. Ambrx Biopharma, Inc. April 19, 2023. Accessed July 19, 2023. https://ir.ambrx.com/news/news-details/2023/Ambrx-Presents-New-Preclinical-Data-on-ARX517-and- ARX305- at-AACR-2023-annual-conference/default.aspx

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