John Shen, MD, medical oncologist, University of California Los Angeles Health Encino Cancer Care, discusses unique features associated with the use of the prostate-specific membrane antigen (PSMA)–directed antibody-drug conjugate (ADC) ARX517 in patients with metastatic castration-resistant prostate cancer (mCRPC) and highlights early efficacy and safety findings with this agent.

The ongoing, first-in-human phase 1/2 APEX-01 trial (NCT04662580) is investigating the safety and preliminary efficacy of ARX517 monotherapy in PSMA-unselected patients with mCRPC whose disease has progressed on at least two prior lines of FDA-approved treatments, with at least one being a second-generation androgen receptor pathway inhibitor, and who have met at least one of the following three criteria: PSA progression defined by a minimum of 2 rising PSA values, radiographic progression by RECIST v1.1 criteria, and/or disease progression by the presence of new bone lesions.

Across all 8 cohorts in APEX-01 (n = 65), grade 3 treatment-related adverse effects (TRAEs) were observed in 6 patients. These TRAEs included lymphocyte count decrease (n = 3), transient platelet count decrease (n = 2), and asymptomatic left ventricular dysfunction (n = 1). No treatment-related grade 3 or higher serious adverse effects occurred.

The tolerability of ARX517 is largely due to the ADC’s stable conjugation, Shen says. Previous research efforts targeting PSMA using other ADCs have been limited, and those ADCs did not progress further in clinical development because of their associated toxicities, Shen notes. Notably, the early findings from the APEX-01 trial show no such toxicity concerns associated with ARX517. Dose-escalation portions of this trial are ongoing to glean additional data regarding the safety profile of this agent, Shen explains.

Additionally, across all patients who received at least 2.0 mg/kg of the study drug, 61% achieved a prostate-specific antigen (PSA) response of 30% or greater, 52% achieved a PSA response of 50% or greater, and 26% achieved a PSA response of 90% or greater.

Although the PSA reductions of more than 50% and more than 90% are encouraging, investigators aim to determine the duration of these responses, particularly in heavily pretreated patients, according to Shen. The trial recently enrolled an additional 40 patients, and the data with these patients will be presented in the future, Shen concludes.

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John Shen, MD, discusses unique features associated with the use of the prostate-specific membrane antigen–directed antibody-drug conjugate ARX517 in patients with metastatic castration-resistant prostate cancer and highlights early efficacy and safety findings with this agent.

Dr Shen on the Tolerability and Efficacy of ARX517 in mCRPC

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 

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.

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.

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%).

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). 

. 2023;34(suppl 2):S974-S975. doi:10.1016/j.annonc.2023.09.2752

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

Articles

ARX517 displayed preliminary efficacy and a strong safety profile in patients with metastatic castration-resistant prostate cancer, according to findings from the phase 1/2 APEX-01 study.

ARX517 Demonstrates Early Efficacy With Favorable Safety in Heavily Pretreated mCRPC

Russell Pachynski, MD, associate professor of medicine, Division of Medical Oncology, Washington University School of Medicine in St Louis, medical oncologist, Siteman Cancer Center, discusses the ongoing investigation of ARX517 in patients with advanced solid tumors, including prostate cancer, in the phase 1/2 APEX-01 trial (NCT04662580).

ARX517 is a novel anti–prostate-specific membrane antigen (PSMA) antibody-drug conjugate comprised of a humanized anti-PSMA monoclonal antibody linked to 2 proprietary microtubule-disrupting toxins (AS269). A first-in-human, multicenter study is currently assessing the safety, pharmacokinetics, and preliminary anti-tumor efficacy of the agent as a monotherapy in patients with advanced solid tumors whose disease has responded to standard therapies, including patients with metastatic castration-resistant prostate cancer (mCRPC), Pachynski details.

In this study, ascending dose levels of ARX517 are administered every 3 weeks. To date, the trial has evaluated 22 patients with prostate cancer distributed across 7 dose level cohorts ranging from 0.32 mg/kg to 2.4 mg/kg, with a minimum of 3 patients in each cohort. The dose limiting toxicity (DLT) assessment period is 21 days.

Initial clinical findings from the phase 1 dose escalation portion of the trial showed that all 3 patients in cohort 6 with metastatic prostate cancer, who received ARX517 at 2.0 mg/kg, experienced a substantial reduction in prostate-specific antigen (PSA) levels, Pachynski reports. PSA was reduced by more than 50% in all 3 patients, with 2 patients experiencing a PSA reduction of over 90%. Importantly, no severe adverse effects (AEs) or dose-limiting toxicities (DLTs) related to the drug were reported, indicating a favorable safety profile, Pachynski states. Based on this safety profile, ARX517 may be more tolerable for this population than prior ADCs due to its unique design and chemical interactions, he notes.

Overall, early results demonstrate the potential efficacy of ARX517 in reducing PSA levels and its tolerability in patients with metastatic prostate cancer, Pachynski concludes. The dose-escalation study is ongoing and continues to enroll patients.

Russell Pachynski, MD, discusses the ongoing investigation of ARX517 in patients with advanced solid tumors in the phase 1/2 APEX-01 trial.
 

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Dr Shen on the Tolerability and Efficacy of ARX517 in mCRPC

ARX517 Demonstrates Early Efficacy With Favorable Safety in Heavily Pretreated mCRPC

Dr Pachynski on the Ongoing Investigation of ARX517 in Advanced Solid Tumors