APEX-01 Looks to Add First PSMA-Directed ADC to Treatment Paradigm in mCRPC

Oncology Live®Vol. 25 No. 4
Volume 25
Issue 4

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John Shen, MD, discusses the phase 1/2 APEX-01 trial of ARX517 in metastatic castration-resistant prostate cancer.

John Shen, MD

John Shen, MD

Although newer agents such as androgen receptor (AR) inhibitors have prolonged survival for patients with metastatic castration-resistant prostate cancer (mCRPC) and gained FDA approval, there remains an unmet need for additional effective therapies in the space, as cross-resistance between treatments can occur and mCRPC remains incurable.1 Investigators are hoping that positive early data from the phase 1/2 APEX-01 trial (NCT04662580) will lead to the eventual addition of the novel antibody-drug conjugate (ADC) ARX517 to the arsenal of agents available for the treatment of patients with mCRPC.

“It’s a very exciting time in mCRPC, [as] there are many novel compounds in [preclinical] study and clinical development,” John Shen, MD, a medical oncologist at University of California, Los Angeles Health, said in an interview with OncologyLive. “[ARX517] has shown encouraging early activity, but we’d love to treat more patients to learn more about its true efficacy. To do that, we’re happy to evaluate more patients for the study.”

ARX517 is a prostate-specific membrane antigen (PSMA)-targeted ADC that has been designed to address the stability issues observed with other PSMA-targeted ADCs, which can lead to severe toxicities due to premature release and off-target delivery of the cytotoxic payload. To increase stability, the developers of ARX517 included a non–cell permeable payload, a noncleavable PEG linker, and unique oxime conjugation chemistry via a genetically encoded and biosynthetically incorporated synthetic amino acid.2

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.3

APEX-01 Study Design

APEX-01 is an open-label, multicenter, first-in-human trial of ARX517 as monotherapy and in combination with enzalutamide (Xtandi) in patients with mCRPC. The study aims to enroll approximately 222 adult patients with mCRPC who are resistant or refractory to prior standard therapies.4,5

To be eligible for enrollment, patients must have castration-resistant disease with serum testosterone levels of 50 ng/dL or lower at screening. Patients who have not undergone an orchiectomy must currently be receiving treatment with either a luteinizing hormone-releasing hormone agonist or antagonist and must consent to maintain this therapy throughout the study treatment. Additionally, patients must have adequate blood counts and have undergone at least 2 FDA-approved treatments for mCRPC, including at least 1 second-generation AR inhibitor.4

Patients will receive intravenous ARX517 every 3 or 4 weeks as monotherapy or combination therapy with enzalutamide in the phase 1 portion of the trial. Phase 1a (the dose-escalation portion) and phase 1b (the dose-expansion portion) will identify the maximum tolerated dose (MTD) and/or the recommended phase 2 doses (RP2Ds). During the phase 2 portion, patients will be randomly assigned to receive ARX517 at the RP2D(s) or the comparator arm consisting of an immune checkpoint inhibitor to be determined after a review of the phase 1 data.4

The primary end point is the incidence of adverse effects (AEs). Secondary end points include the area under the serum concentration-time curve for ARX517 and enzalutamide, maximum serum concentration for both agents, trough concentration for both agents, the incidence of antidrug antibodies against ARX517, overall survival, changes in serum prostate-specific antigen (PSA) levels, and progression-free survival. Exploratory end points include biomarker evaluation and PSMA expression.4

Preclinical Data Support Study Rationale

During the European Society for Medical Oncology (ESMO) Congress 2023, which took place from October 20 to 24 in Madrid, Spain, investigators presented 2 abstracts that demonstrated strong preclinical findings with ARX517.

Findings from Tagawa et al showed that ARX517 displayed a long terminal half-life of approximately 6 to 10 days at doses of at least 1.4 mg/kg, leading to maximal agent exposure. Additionally, ARX517 demonstrated strong stability in circulation. Investigators noted the agent displayed virtually overlapping total antibody and ADC pharmacokinetic concentration-time curves across examined doses, and this was the first anti-PSMA ADC to display strong stability in circulation. They explained that the technology utilized by the agent has the potential to be used in the development of the next generation of ADCs to improve efficacy and minimize toxicity.2

“The most important takeaway is the stable conjugation of this compound,” Shen said. “Several earlier attempts to target PSMA with prior ADCs were limited and didn’t progress into further clinical development due to early toxicity.”

Additional data was presented at ESMO regarding the preclinical antitumor activity of ARX517 in enzalutamide-resistant and enzalutamide-sensitive tumor models, as well as in a nonhuman primate model.6 In the enzalutamide-sensitive model, treatment with ARX517 at doses of 1 mg/kg and 3 mg/kg led to a reduction in tumor volume of 28% and 66%, respectively, compared with 42% for enzalutamide at 10 mg/kg. In the enzalutamide-resistant model, the tumor volume reduction rates for ARX517 at 1 mg/kg and 3 mg/kg were 37% and 79%, respectively, vs 14% with enzalutamide at 10 mg/kg.6

Early Findings From APEX-01 Reveal Preliminary Efficacy, Tolerability

Building on the preclinical data presented during ESMO, Shen also shared preliminary findings from APEX-01 in a poster presentation. At the September 5, 2023, data cutoff, a total of 65 patients were enrolled across different cohorts. Patients received ARX517 at doses of 0.32 mg/kg (cohort 1; n = 1), 0.64 mg/kg (cohort 2; n = 3), 1.07 mg/kg (cohort 3; n = 3), 1.4 mg/kg (cohort 4; n = 21), 1.7 mg/kg (cohort 5; n = 5), 2.0 mg/kg (cohort 6; n = 20), 2.4 mg/kg (cohort 7; n = 6), and 2.88 mg/kg (cohort 8; n = 6).5

At baseline, the median age across cohorts was 68.0 years (range, 50-100), the median PSA level was 47.0 μg/L (range, 1-3845), and the median number of prior AR inhibitor treatments was 2 (range, 1-5). Most patients received a prior taxane (66%), did not receive a prior immunotherapy (54%), did not receive a prior PSMA-targeted radionuclide therapy (TRT; 83%), and had an ECOG performance status of 1 (59%). Regarding second-generation AR inhibitors, patients were previously treated with abiraterone acetate (Zytiga; 75%), enzalutamide (69%), and both abiraterone acetate and enzalutamide (48%).5

Findings from the study showed that deep PSA reductions were present with increasing doses of ARX517; among patients treated in cohorts 6 through 8 (n = 23), at what investigations deemed to be putative doses, PSA reductions of at least 30% (PSA30), 50% (PSA50), and 90% (PSA90) occurred at rates of 61%, 52%, and 26%, respectively. Comparatively, patients treated in cohorts 1 through 3 (n = 7) experienced PSA30, PSA50, and PSA90 rates of 29%, 0%, and 0%, respectively.5

Additionally, 81% of evaluable patients given putative doses (n = 21) experienced reductions of at least 50% in circulating tumor DNA at a rate of 81%. Among patients with evaluable target lesions at baseline (n = 9), target lesion reduction occurred at a rate of 56% in 5 patients, including 2 confirmed responses per RECIST 1.1 criteria. Notably, PSA reductions of 50% or greater were achieved in patients who underwent prior PSMA-TRT and received a dose of at least 2 mg/kg (n = 6) at a rate of 50%.5

“Deep PSA reductions have been seen with increasing ARX517 doses,” Shen said. “This included patients who had received prior PSMA-[TRT], and we’re still seeing significant PSA reductions in several of those patients.”

In terms of safety, patients in all cohorts experienced any-grade treatment-related AEs (TRAEs) at a rate of 74% and grade 3 TRAEs at a rate of 9%. Two patients experienced AEs leading to treatment discontinuation. No patients experienced serious AEs or grade 4/5 AEs. Notably, no dose-limiting toxicities were reported.5

Treatment-related decreased lymphocyte count (5%), decreased platelet count (3%), and left ventricular dysfunction (2%) were reported sparingly. Common grade 1 or 2 TRAEs across dose levels included dry mouth (28%), dry eye (22%), fatigue (20%), and diarrhea (15%).5

Study authors concluded that ARX517 monotherapy demonstrated a favorable safety profile with early efficacy, absent of PSMA imaging selection, among patients with mCRPC who experienced disease progression on multiple FDA-approved treatments. They highlighted that an expansion of cohort 8 and an escalation into the next higher dose (cohort 9) are planned.5

“We’re continuing to dose escalate and learn more about this compound,” Shen said. “However, the stable conjugation of this ADC is the most encouraging feature. In terms of efficacy, we love seeing PSA50s and PSA90s, but ultimately, we’d like to see how long patients can sustain those for in a heavily pretreated patient population.”

Shen noted that an additional 40 patients have been enrolled in APEX-01 in recent months and that additional data will be read out at a future medical meeting. “[ARX517] could become, in some ways, a replacement for taxane chemotherapy,” Shen said in conclusion. “Of course, we don’t know that, and we need to study that question. However, I could see this as a first-line mCRPC treatment option eventually. This is a very early look at the data, and it’s encouraging to see that it has demonstrated safety and tolerability. But we have not yet reached the MTD [or] the RP2D. We’re continuing to expand into higher cohorts and dose escalation.”


  1. Hatano K, Nonomura N. Systemic therapies for metastatic castration-resistant prostate cancer: an updated review. World J Mens Health. 2023;41(4):769-784. doi:10.5534/wjmh.220200
  2. Tagawa ST, Shen J, Skidmore L, et al. ARX517: a next generation anti-PSMA antibody drug conjugate (ADC) demonstrates notable stability and pharmacokinetic (PK) profile in the ARX517 phase I clinical trial (APEX-01). Ann Oncol. 2023;34(suppl 2):S990. doi:10.1016/j.annonc.2023.09.2776
  3. FDA awards fast track designation to ARX517 for metastatic castration-resistant prostate cancer. News release. FDA. July 19, 2023. Accessed November 20, 2023. bit.ly/3MWljka
  4. ARX517 as monotherapy and in combination regimens in subjects with metastatic castration-resistant prostate cancer (ARX517). ClinicalTrials.gov. Updated November 22, 2023. Accessed November 20, 2023. https://clinicaltrials.gov/study/NCT04662580
  5. Shen J, Pachynski R, Nordquist L, 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
  6. Zhang S, Mills D, Kim JY, et al. Evaluation of ARX517: a next-generation anti-PSMA antibody drug conjugate for prostate cancer treatment, in preclinical enzalutamide-resistant and enzalutamide-sensitive pharmacology models and in toxicology models. Ann Oncol. 2023;34(suppl 2):S199. doi:10.1016/j.annonc.2023.09.1543
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