PSMA ADC monotherapy in patients with progressive metastatic castration-resistant prostate cancer following abiraterone and/or enzalutamide: Efficacy and safety in open-label single-arm phase 2 study.

Prostate-specific membrane antigen (PSMA) is a well-established therapeutic and diagnostic target overexpressed in both primary and metastatic prostate cancers. PSMA antibody-drug conjugate (PSMA ADC) is a fully human immunoglobulin G1 anti-PSMA monoclonal antibody conjugated to monomethylauristatin E, which binds to PSMA-positive cells and induces cytotoxicity. In a phase 1 study, PSMA ADC was well tolerated and demonstrated activity as measured by reductions in serum prostate-specific antigen (PSA) and circulating tumor cells (CTCs). To further assess PSMA ADC, we conducted a phase 2 trial in metastatic castration-resistant prostate cancer (mCRPC) subjects who progressed following abiraterone/enzalutamide (abi/enz) therapy.

A total of 119 (84 chemotherapy-experienced and 35 chemotherapy-naïve) subjects were administered PSMA ADC 2.5 or 2.3 mg/kg IV q3w for up to eight cycles. Antitumor activity (best percentage declines in PSA and CTCs from baseline and tumor responses through radiological imaging), exploratory biomarkers, and safety (monitoring of adverse events [AEs], clinical laboratory tests, and Eastern Cooperative Oncology Group performance status) were assessed.

PSA declines ≥50% occurred in 14% of all treated (n = 113) and 21% of chemotherapy-naïve subjects (n = 34). CTC declines ≥50% were seen in 78% of all treated (n = 77; number of subjects with ≥5 CTCs at baseline and a posttreatment result) and 89% of chemotherapy-naïve subjects (n = 19); 47% of all treated and 53% of chemotherapy-naïve subjects had a transition from ≥5 to less than 5 CTCs/7.5 mL blood at some point during the study. PSA and CTC reductions were associated with high PSMA expression (CTCs or tumor tissue) and low neuroendocrine serum markers. In the chemotherapy-experienced group, the best overall radiologic response to PSMA ADC treatment was stable disease in 51 (60.7%) subjects; 5.7% of subjects in the chemotherapy-naïve group had partial responses. The most common treatment-related AEs ≥Common Terminology Criteria for AE (CTCAE) grade 3 were neutropenia, fatigue, electrolyte imbalance, anemia, and neuropathy. The most common serious AEs were dehydration, hyponatremia, febrile neutropenia, and constipation. Two subjects who received 2.5 mg/kg died of sepsis.

PSMA ADC demonstrated some activity with respect to PSA declines, CTC conversions/reductions, and radiologic assessments in abi/enz treated mCRPC subjects. Clinically significant treatment-related AEs included neutropenia and neuropathy.

The Prostate. 2019 Nov 19 [Epub ahead of print]

Daniel P Petrylak, Nicholas J Vogelzang, Kamal Chatta, Mark T Fleming, David C Smith, Leonard J Appleman, Arif Hussain, Manuel Modiano, Parminder Singh, Scott T Tagawa, Ira Gore, Edward F McClay, Anthony E Mega, A Oliver Sartor, Bradley Somer, Raymond Wadlow, Neal D Shore, William C Olson, Nancy Stambler, Vincent A DiPippo, Robert J Israel

Department of Urology, Yale University, New Haven, Connecticut., Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada., Virginia Mason Medical Center, Seattle, Washington., Virginia Oncology Associates, Norfolk, Virginia., University of Michigan, Ann Arbor, Michigan., Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania., University of Maryland, Baltimore, Maryland., Arizona Clinical Research Center, Tucson, Arizona., Mayo Clinic, Phoenix, Arizona., Weill Cornell Medical College, New York, New York., Alabama Oncology, Birmingham, Alabama., California Cancer Associates for Research and Excellence, Encinitas, California., The Miriam Hospital, Providence, Rhode Island., School of Medicine, Tulane University, New Orleans, Louisiana., West Cancer Center and Research Institute, Memphis, Tennessee., Virginia Cancer Specialists, Fairfax, Virginia., Carolina Urologic Research Center, Myrtle Beach, South Carolina., Progenics Pharmaceuticals, Inc, New York, New York.