Antibody-Drug Conjugate Has Antitumor Activity in Metastatic Castration-Resistant Prostate Cancer
“By conjugating the antibody with a chemotherapeutic agent, we hoped that this would lead to more targeted therapy, which would have fewer toxic side effects and would be more effective against the cancer,” said Daniel Petrylak, MD, Director of the Prostate Cancer Program/Genitourinary Cancer Program and co-director of the Signal Transduction Program at Yale University Medical Center, New Haven, CT.
PSMA ADC is a fully human antibody to PSMA linked to the potent antitubulin agent monomethyl auristatin E (MMAE), which binds to PSMA and is internalized within the prostate cancer cell, where cleavage by lysosomal enzymes (Cathepsin B) releases free MMAE, causing cell cycle arrest and apoptosis.
In the phase 1 dose escalation study, PSMA ADC was administered by IV infusion every 3 weeks for up to 4 cycles; 50 subjects were dosed in 9 dose levels. Dose-limiting toxicity was observed at 2.8mg/kg, including 1 death from neutropenia (cause unclear) and reversible LFT elevations.
Antitumor activity manifested as reductions in either prostate-specific antigen (PSA) or circulating tumor cells (CTCs) in the higher dose cohorts. PSA reductions of >50% and/or reductions in CTCs to <5 cells/7.5mL blood have been observed in approximately 50% of patients at doses of ≥1.8mg/kg.
“These results show that PSMA ADC has antitumour activity in patients who have failed up to two prior chemotherapies and hormone therapy,” Dr. Petrylak said. “We have initiated a phase 2 trial of up to 75 patients in which the recommended dose will be 2.5 mg/kg. This new trial will evaluate responses in PSA and CTC; it will evaluate control of metastases in bone, internal organs and lymph nodes; and it will look at the effect on pain. Safety also will be assessed.
“The fact that this new targeted therapy is active against the most advanced forms of prostate cancer is encouraging, as few or no therapeutic options are available at present.”
Prof. Stefan Sleijfer, Erasmus University Medical Center, The Netherlands, scientific chair of the EORTC-NCI-AACR Symposium, commented: “The approach tested here represents a novel way to treat prostate cancer. The antitumor effects already seen at such an early phase of clinical testing, such as a fall in circulating tumour cells, render this drug a promising compound for prostate cancer.”
Abstract (select Abstract #244)