Full results from a Phase II clinical trial of PSMA ADC (Progenics Pharmaceuticals, Inc., Tarrytown, NY, USA), a fully human monoclonal antibody-drug conjugate, in patients with metastatic castration-resistant prostate cancer (mCRPC) presented at the American Society of Clinical Oncology Genitourinary Cancers (ASCO GU) Symposium, which was being held February 26 – 28, 2015 in Orlando, Florida, showed that treatment with this trial drug produces clinically relevant declines in PSA and CTC counts and radiologic responses in both taxane-experienced and chemo-naïve patients. 
Prostate cancer is the second most common form of cancer affecting men in the United States. An estimated one in six men will be diagnosed with prostate cancer in his lifetime. According to the American Cancer Society approximately 240,000 new cases of prostate cancer will be diagnosed and about 30,000 men will die of the disease this year. The same data suggest that approximately two million men in the U.S. currently can count themselves among prostate cancer survivors.
A targeted approach
PSMA ADC is fully human IgG1 antibody designed to delivers the chemotherapeutic drug selectively to prostate cancer cells. It does so by targeting the three-dimensional structure of the prostate specific membrane antigen or PSMA, a protein that is a clinically validated biomarker of prostate cancer and which is overexpressed on the surface of prostate cancer cells.
The PSMA antibody is linked to the chemotherapeutic microtubule disrupting agent monomethyl auristatin E (MMAE), which inhibits cell proliferation by disrupting the cellular “backbone” required for replication. The resultant antibody-drug conjugate attaches itself to the PSMA-protein on the surface of prostate cancer cells and is designed to internalize into the cancer cell, release the active anti-cancer drug, and destroy the malignant cell.
The poster presentation included the full data from the Phase II trial, including the final results from the recently completed chemo-naïve cohort and detailed PSA, CTC and radiological data.
In addition to preliminary data demonstrating that treatment with PSMA ADC produces clinically relevant declines in PSA and CTC counts and radiologic responses in both taxane-experienced and chemo-naïve patients, the trial results also showed that efficacy responses were associated with high PSMA expression (CTCs or tumor tissue) and low neuroendocrine serum markers. The researchers also clarified that the one death in the 2.3mg/kg group that was initially attributed to sepsis in the abstract was later determined to be related to progression of disease.
Phase II study
A previous phase I study showed activity and tolerability at doses from 1.8-2.5 mg/kg. For this phase II trial, the researchers enrolled 119 mCRPC patients (83 taxane experienced and 36 chemo-naïve who progressed following taxane and abiraterone and/or enzalutamide regimens. Patients with ECOG PS 0, 1 or 2 were eligible. 
To participate, patients who were cytotoxic chemotherapy-naïve must have received and progressed on-, be ineligible for, refused, have an intolerance to-, or not have access to Radium-223.
As part of the trial, metastatic castration-resistant prostate cancer (mCRPC) were administered PSMA ADC 2.5 or 2.3 mg/kg IV Q3 week for up to 8 cycles. 95% of pts received prior abiraterone and/or enzalutamide treatment. Safety, antitumor activity (including PSA, CTCs, and tumor imaging) and exploratory biomarkers were assessed.
The trial results showed that in all treated patients, a PSA decline of ≥30% and ≥50% were 30% and 14%, respectively (n=113). Furthermore, CTC counts showed a decline of ≥50% in 78% of patients and conversion from ≥5 to <5 cells/7.5 ml blood in 47% (n=77) at any time during the study.
For 2.3 mg/kg pts (n=82), corresponding PSA declines were 35% and 17% and CTC declines of ≥50% were seen in 81% and conversions in 46% (n=54).
For chemo-naïve patients, PSA declines of ≥30% and ≥50% were 31% and 20% (n=35); CTC declines of ≥50% were seen in 89% and conversion in 53% (n=19). Radiologic response by RECIST (Response Evaluation Criteria In Solid Tumors) in 31 patients with measurable target lesions: PR in 4 patients, SD in 19 patients, and PD in 8 patients.
Efficacy and Adverse Events
Trial efficacy responses were associated with low neuroendocrine serum markers (low CgA, low NSE, and high PSA), and high PSMA expression (CTCs or tumor tissue). The most common treatment-related adverse events ≥CTC AE grade 3 were neutropenia (TE: 25%; CN: 22%), fatigue (20%; 8%), electrolyte imbalance (16%; 11%), anemia (10%; 8%), and neuropathy (8%; 8%). Grade 1-2 neuropathy occurred in 40% (TE) and 50% (CN) of patients. The results also showed that two 2.5 mg/kg pts (n=34) died of sepsis. Overall, the results showed that 2.3 mg/kg was better tolerated than 2.5 mg/kg.
Based on the trial results, the researchers concluded that PSMA ADC was active in abiraterone and/or enzalutamide refractory mCRPC patients. Clinically significant therapy related adverse events included neutropenia and neuropathy. CTC conversions/reductions, PSA declines, and radiologic evidence of antitumor activity were seen in CN as well as heavily pretreated patients.