ENZA-p: A randomized phase II trial using PSMA as a therapeutic agent and prognostic indicator in men with metastatic castration-resistant prostate cancer treated with enzalutamide (ANZUP 1901).
Authors: Louise Emmett, Shalini Subramaniam, Alison Yan Zhang, Andrew James Martin, Sonia Yip, Megan Crumbaker, Nisha Rana, Kate Ford, Ailsa Langford, Roslyn J. Francis, Michael S Hofman, Anthony M. Joshua, Shahneen Kaur Sandhu, Arun Azad, Craig Gedye, Margaret Mary McJannett, Martin R. Stockler, Ian D. Davis
Journal: Journal of Clinical Oncology (2021)

TPS177 Background: 177 Lu‐PSMA‐617 (LuPSMA) is a novel radionuclide with promising activity and tolerability in metastatic, castration-resistant prostate cancer (mCRPC). Pre-clinical studies have shown that androgen receptor blockade with enzalutamide upregulates PSMA-receptor expression, and that PSMA-receptor blockade increases treatment response to enzalutamide. We hypothesise that concurrent administration of LuPSMA and enzalutamide will be synergistic in mCRPC. The aims of ENZA-p are to determine the activity and safety of LuPSMA and enzalutamide in men with mCRPC at high-risk of early progression on enzalutamide alone; and to identify potential prognostic and predictive biomarkers from imaging, blood, and tissue. Methods: This open-label, randomised, multicentre, phase 2 trial will recruit 160 men with mCRPC. Key eligibility criteria include progression on androgen deprivation therapy, 2 or more high-risk features for early (LDH ≥ULN; ALP ≥ULN; albumin &lt;35 g/L; M1 disease at diagnosis; &lt;3 years from initial diagnosis to randomisation; &gt;5 bone metastases; visceral metastases; PSA doubling time &lt;84 days; pain requiring opiates &gt;14 days; prior abiraterone), no prior treatment with a novel androgen signalling inhibitor (except abiraterone), no prior chemotherapy for mCRPC, and PSMA-avid disease on positron emission tomography (PET) with 68 Ga-PSMA. Participants are randomly assigned (1:1) enzalutamide 160 mg daily or enzalutamide 160 mg daily plus LuPSMA 7.5 GBq on days 15 and 57. Two subsequent doses of Lu-PSMA will be administered if the 68 Ga-PSMA PET on day 92 shows persistent PSMA expression in the tumour. Imaging assessments include CT and technetium bone scan at baseline, day 99, then every 12 weeks; 68 Ga-PSMA-11 PET at baseline, days 15, 92, and first progression; and 18 F FDG PET at baseline and first progression. Translational samples including circulating tumour cells (CTCs), circulating tumour DNA (ctDNA) and biopsies (optional) will be collected at baseline, day 92, and first progression. The primary endpoint is PSA progression-free survival (PSA-PFS). Secondary endpoints include radiological-PFS, PSA-response rate, pain response and PFS, clinical-PFS, overall survival, health related quality of life, adverse events, and cost-effectiveness. Correlative studies include identification of prognostic and predictive biomarkers from 68 Ga-PSMA, 18 F FDG PET/CT, CTCs, and ctDNA. A sample size of 160 provides 80% power with a 2-sided type 1-error rate of 5% to detect a HR of 0.625 assuming a median PSA-PFS of 5 months with enzalutamide alone. Accrual was 5 on 13 October 2020. ENZA-p is an investigator-initiated, academic trial led by ANZUP in collaboration with the NHMRC Clinical Trials Centre, University of Sydney. Clinical trial information: NCT04419402.