PMID- 31742767 OWN - NLM STAT- MEDLINE DCOM- 20200413 LR - 20211204 IS - 1097-0045 (Electronic) IS - 0270-4137 (Linking) VI - 80 IP - 1 DP - 2020 Jan TI - 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. PG - 99-108 LID - 10.1002/pros.23922 [doi] AB - BACKGROUND: 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. METHODS: A total of 119 (84 chemotherapy-experienced and 35 chemotherapy-naive) 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. RESULTS: PSA declines >/=50% occurred in 14% of all treated (n = 113) and 21% of chemotherapy-naive 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-naive subjects (n = 19); 47% of all treated and 53% of chemotherapy-naive 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-naive 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. CONCLUSIONS: 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. CI - (c) 2019 Wiley Periodicals, Inc. FAU - Petrylak, Daniel P AU - Petrylak DP AD - Department of Urology, Yale University, New Haven, Connecticut. FAU - Vogelzang, Nicholas J AU - Vogelzang NJ AD - Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada. FAU - Chatta, Kamal AU - Chatta K AD - Virginia Mason Medical Center, Seattle, Washington. FAU - Fleming, Mark T AU - Fleming MT AD - Virginia Oncology Associates, Norfolk, Virginia. FAU - Smith, David C AU - Smith DC AD - University of Michigan, Ann Arbor, Michigan. FAU - Appleman, Leonard J AU - Appleman LJ AD - Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania. FAU - Hussain, Arif AU - Hussain A AD - University of Maryland, Baltimore, Maryland. FAU - Modiano, Manuel AU - Modiano M AD - Arizona Clinical Research Center, Tucson, Arizona. FAU - Singh, Parminder AU - Singh P AD - Mayo Clinic, Phoenix, Arizona. FAU - Tagawa, Scott T AU - Tagawa ST AD - Weill Cornell Medical College, New York, New York. FAU - Gore, Ira AU - Gore I AD - Alabama Oncology, Birmingham, Alabama. FAU - McClay, Edward F AU - McClay EF AD - California Cancer Associates for Research and Excellence, Encinitas, California. FAU - Mega, Anthony E AU - Mega AE AD - The Miriam Hospital, Providence, Rhode Island. FAU - Sartor, A Oliver AU - Sartor AO AUID- ORCID: 0000-0002-8777-7343 AD - School of Medicine, Tulane University, New Orleans, Louisiana. FAU - Somer, Bradley AU - Somer B AD - West Cancer Center and Research Institute, Memphis, Tennessee. FAU - Wadlow, Raymond AU - Wadlow R AD - Virginia Cancer Specialists, Fairfax, Virginia. FAU - Shore, Neal D AU - Shore ND AD - Carolina Urologic Research Center, Myrtle Beach, South Carolina. FAU - Olson, William C AU - Olson WC AD - Progenics Pharmaceuticals, Inc, New York, New York. FAU - Stambler, Nancy AU - Stambler N AD - Progenics Pharmaceuticals, Inc, New York, New York. FAU - DiPippo, Vincent A AU - DiPippo VA AUID- ORCID: 0000-0002-5529-4195 AD - Progenics Pharmaceuticals, Inc, New York, New York. FAU - Israel, Robert J AU - Israel RJ AD - Progenics Pharmaceuticals, Inc, New York, New York. LA - eng PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20191119 PL - United States TA - Prostate JT - The Prostate JID - 8101368 RN - 0 (Androstenes) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Benzamides) RN - 0 (Biomarkers, Tumor) RN - 0 (Immunotoxins) RN - 0 (Nitriles) RN - 0 (PSMA ADC) RN - 2010-15-3 (Phenylthiohydantoin) RN - 93T0T9GKNU (enzalutamide) RN - G819A456D0 (abiraterone) SB - IM MH - Aged MH - Aged, 80 and over MH - Androstenes/administration & dosage MH - Antibodies, Monoclonal, Humanized/adverse effects/*therapeutic use MH - Antineoplastic Combined Chemotherapy Protocols/administration & dosage MH - Benzamides MH - Biomarkers, Tumor/blood MH - Drug Resistance, Neoplasm MH - Humans MH - Immunotoxins/adverse effects/therapeutic use MH - Male MH - Middle Aged MH - Nitriles MH - Phenylthiohydantoin/administration & dosage/analogs & derivatives MH - Prostatic Neoplasms, Castration-Resistant/blood/diagnostic imaging/*drug therapy MH - Survival Rate MH - Treatment Outcome OTO - NOTNLM OT - antibody-drug conjugate OT - mCRPC OT - prostate-specific membrane antigen EDAT- 2019/11/20 06:00 MHDA- 2020/04/14 06:00 CRDT- 2019/11/20 06:00 PHST- 2019/08/30 00:00 [received] PHST- 2019/10/16 00:00 [accepted] PHST- 2019/11/20 06:00 [pubmed] PHST- 2020/04/14 06:00 [medline] PHST- 2019/11/20 06:00 [entrez] AID - 10.1002/pros.23922 [doi] PST - ppublish SO - Prostate. 2020 Jan;80(1):99-108. doi: 10.1002/pros.23922. Epub 2019 Nov 19.