ENZA-p trial protocol: a randomized phase II trial using prostate-specific membrane antigen as a therapeutic target and prognostic indicator in men with metastatic castration-resistant prostate cancer treated with enzalutamide (ANZUP 1901).

OBJECTIVES: To determine the activity and safety of lutetium-177 (177 Lu)-prostate-specific membrane antigen (PSMA)-617 in men with metastatic castration-resistant prostate cancer (mCRPC) commencing enzalutamide, who are at high risk of early progression, and to identify potential prognostic and predictive biomarkers from imaging, blood and tissue. PARTICIPANTS AND METHODS: ENZA-p (ANZUP 1901) is an open-label, randomized, two-arm, multicentre, phase 2 trial. Participants are randomly assigned (1:1) to treatment with enzalutamide 160 mg daily alone or enzalutamide plus 177 Lu-PSMA-617 7.5 GBq on Days 15 and 57. Two additional 177 Lu-PSMA-617 doses are allowed, informed by Day-92 Gallium-68 (68 Ga)-PSMA positron emission tomography (PET; up to four doses in total). The primary endpoint is prostate-specific antigen (PSA) progression-free survival (PFS). Other major endpoints include radiological PFS, PSA response rate, overall survival, health-related quality of life, adverse events and cost-effectiveness. Key eligibility criteria include: biochemical and/or clinical progression; 68 Ga-PSMA PET-avid disease; no prior androgen signalling inhibitor, excepting abiraterone; no prior chemotherapy for mCRPC; and ≥2 high-risk features for early enzalutamide failure. Assessments are 4 weekly during study treatment, then 6 weekly until radiographic progression. Response Evaluation Criteria in Solid Tumours (RECIST) are used to assess imaging conducted every 12 weeks, 68 Ga-PSMA PET at baseline, Days 15 and 92, and at progression, and 18 F-fluorine deoxyglucose (18 F-FDG) PET at baseline and progression. Translational samples include blood (and optional biopsies) at baseline, Day 92, and first progression. Correlative studies include identification of prognostic and predictive biomarkers from 68 Ga-PSMA and 18 F-FDG PET/CT, circulating tumour cells and circulating tumour DNA. The trial will enrol 160 participants, providing 80% power with a two-sided type-1 error rate of 5% to detect a hazard ratio of 0.625 assuming a median PSA-PFS of 5 months with enzalutamide alone. RESULTS AND CONCLUSION: The combination of 177 Lu-PSMA-617 and enzalutamide may be synergistic. ENZA-p will determine the safety and efficacy of the combination in addition to developing predictive and prognostic biomarkers to better guide treatment decisions.

Assessment of the role of Ga-68 PSMA I&T PET/CT in response evaluation to docetaxel therapy in castration resistant prostate cancer patients. / Evaluación del papel de la PET/TC con [68Ga]Ga-PSMA I&T en la evaluación de la respuesta a la terapia con docetaxel en pacientes con cáncer de próstata resistente a la castración.

OBJECTIVE: There have been only few studies investigating the role of PSMA ligands in the therapy response assessment of metastasized castration resistant prostate cancer (mCRPC) cases. In this study we aimed at evaluating the capability of 68Ga- prostate-specific membrane antigen (PSMA) I&T positron emission tomography/computerized tomography (PET/CT) in the assessment of therapeutic response in patients under docetaxel therapy for prostate cancer (PCa). MATERIAL AND METHODS: The clinical records of all mCRPC patients treated with docetaxel and referred to our department for 68Ga-PSMA I&T PET/CT imaging were retrospectively analysed. Sixteen patients (mean age 69 years, range 52-82 years) with castration-resistant prostate cancer patients receiving palliative docetaxel therapy and had undergone 68Ga-PSMA I&T PET/CT scan were included in the study. 68Ga-PSMA I&T PET/CT imaging was done and prostate specific antigen (PSA) levels were measured at baseline before administration of docetaxel (PET1) and after at least 3 cycles (range 4-12) of chemotherapy (PET2). Patient-based as well as lesion-based comparison of PET2 findings with PET1 findings were done. RESULTS: The change (decrease) observed in lymph node and prostate gland/prostatic bed SUVmax values after treatment compared to pretreatment was found to be statistically significant (P=.033). 3/16 patients (19%) were classified as progressive disease (PD), 4/16 (25%) as stable disease (SD), 9/16 (56%) as partial remission (PR) radiologically. An increasing PSA trend (IT) was observed in 4 patients (25%) and a decreasing PSA trend (DT) in 3 patients (18%). Nine patients showed a PSA response of ≥ 50% (56%). Of the 4 patients showing SD, 3 had IT, 3 had BR. Of the 9 patients who showed PR on PET studies, 8 patients showed BR and 1 patient showed DT. CONCLUSION: Imaging with 68Ga-PSMA PET/CT showed great concordance with biochemical response evaluation in terms of PSA levels, especially in patients showing good response to therapy. 68Ga-PSMA PET/CT was also successful in identifying progressive disease in patients showing paradoxical decline in PSA levels.

Assessment of the radiation absorbed dose produced by 177Lu-iPSMA, 225Ac-iPSMA and 223RaCl2 to prostate cancer cell nuclei in a bone microenvironment model.

This research aimed to assess the radiation absorbed dose produced by 177Lu-iPSMA (177Lu-prostate specific membrane antigen inhibitor), 225Ac-iPSMA and 223RaCl2 to prostate cancer cell nuclei in a simplified model of bone by using an experimental in-vitro prostate cancer LNCaP cell biokinetic study and Monte Carlo simulation with the MCNPX code. Results showed that 225Ac-iPSMA releases a nine hundred-fold radiation dose greater than 177Lu-iPSMA and 14 times more than 223RaCl2 per unit of activity retained in bone. 225Ac-iPSMA could be the best option for treatment of bone metastases in prostate cancer.

Assessment of an 18F-labeled phosphoramidate peptidomimetic as a new prostate-specific membrane antigen-targeted imaging agent for prostate cancer.

UNLABELLED: Prostate-specific membrane antigen (PSMA) is a transmembrane protein commonly found on the surface of late-stage and metastatic prostate cancer and a well-known imaging biomarker for staging and monitoring therapy. Although (111)In-labeled capropmab pendetide is the only approved agent available for PSMA imaging, its clinical use is limited because of its slow distribution and clearance that leads to challenging image interpretation. A small-molecule approach using radiolabeled urea-based PSMA inhibitors as imaging agents has shown promise for prostate cancer imaging. The motivation of this work is to explore phosphoramidates as a new class of potent PSMA inhibitors to develop more effective prostate cancer imaging agents with improved specificity and clearance properties. METHODS: N-succinimidyl-4-(18)F-fluorobenzoate ((18)F-SFB) was conjugated to S-2-((2-(S-4-amino-4-carboxybutanamido)-S-2-carboxyethoxy)hydroxyphosphorylamino)-pentanedioic acid (Phosphoramidate (1)), yielding S-2-((2-(S-4-(4-(18)F-fluorobenzamido)-4-carboxybutanamido)-S-2-carboxyethoxy)hydroxyphosphorylamino)-pentanedioic acid (3). In vivo studies were conducted in mice bearing either LNCaP (PSMA-positive) or PC-3 (PSMA-negative) tumors. PET images were acquired at 1 and 2 h with or without a preinjection of a nonradioactive version of the fluorophosphoramidate. Tissue distribution studies were performed at the end of the 2 h imaging sessions. RESULTS: Phosphoramidate (1) and its fluorobenzamido conjugate (2) were potent inhibitors of PSMA (inhibitory concentration of 50% [IC(50)], 14 and 0.68 nM, respectively). PSMA-mediated tumor accumulation was noted in the LNCaP versus the PC-3 tumor xenografts. The LNCaP tumor uptake was also blocked by the administration of nonradioactive (2) prior to imaging studies. With the exception of the kidneys, tumor-to-tissue and tumor-to-blood ratios were greater than 5:1 at 2 h. The strong kidney uptake may be due to the known PSMA expression in the mouse kidney, because significant reduction (>6-fold) in kidney activity was seen in mice injected with (2). CONCLUSION: (18)F-labeled phosphoramidate (3) is a representative of a new class of PSMA targeting peptidomimetic molecules that shows great promise as imaging agents for detecting PSMA+ prostate tumors.

Conformational and SAR analysis of NAALADase and PSMA inhibitors.

Prostate specific membrane antigen (PSMA) is a 110 kDa type II transmembrane protein that is expressed exclusively by prostate tumor cells and as such is a clear cellular target in the development of a new method for fast and reliable diagnosis of prostate cancer. PSMA is highly homologous to the neuropeptidase NAALADase, and it has been shown that inhibitors of NAALADase also strongly bind to PSMA. In an effort to better understand the structural basis of the inhibitory activity of more than 60NAALADase inhibitors synthesized and tested by our group, we used Monte Carlo calculations employing the Merck Molecular Force Field to explore the conformational space available to a set of PSMA inhibitors. Conformational analysis indicated that the lower the number of unique conformations accessible by an inhibitor, the greater the biological activity displayed by the compound against LnCAP cells. This suggests that the difference in activity is largely entropy based. The key conformations associated with high activity are used to develop a simple pharmacophore model that led to the design of new, conformationally restricted analogues with potentially high activity in rational drug design.