No abstract

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) progressionfree 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 ConclusionThe 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.

TPS177 Background: 177Lu‐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 <35 g/L; M1 disease at diagnosis; <3 years from initial diagnosis to randomisation; >5 bone metastases; visceral metastases; PSA doubling time <84 days; pain requiring opiates >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 68Ga-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 68Ga-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; 68Ga-PSMA-11 PET at baseline, days 15, 92, and first progression; and 18F 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 68Ga-PSMA, 18F 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.

TPS271 Background: Combination immune checkpoint inhibitors (ICI) with ipilimumab and nivolumab has been shown to induce adaptive immune responses in patients with mCRPC, albeit resulting in modest clinical benefit. There is growing evidence that radiation may enhance the activity of ICI by modulating the tumour immune microenvironment. We hypothesize that the radionuclide 177Lu-PSMA-617 may result in immunogenic cell death and therefore synergise with combination ICI to improve long term clinical outcomes. EVOLUTION aims to determine the activity and safety of ipilimumab and nivolumab in combination with 177Lu-PSMA-617 in patients with mCRPC. Methods: This open label, multicentre, phase 2 study will randomly assign 100 participants with mCRPC in a 2:1 ratio stratified by site and prior exposure to docetaxel to either: the experimental combination of 177Lu-PSMA-617 7.5 GBq every 6 weeks for up to 6 doses plus ipilimumab 3 mg/kg every 6 weeks x 4 doses and nivolumab 1 mg/kg every 3 weeks x 8 doses during induction, followed by nivolumab 480 mg every 4 weeks x 18 doses during maintenance or 177Lu-PSMA-617 alone. Key eligibility criteria include progression on prior androgen receptor pathway inhibitors, no more than one line of prior chemotherapy, significant PSMA avidity on 68GaPSMA-11 PET/CT (SUVmax ≥15 at one disease site and SUVmax ≥10 at measurable sites of disease > 10 mm), no FDG positive/PSMA negative disease and no contraindications to ICI. The primary endpoint is 12-month PSA progression-free survival (PSA-PFS). Secondary endpoints are PSA response rate, adverse events, radiographic-PFS, overall survival, objective response rate, duration of response and health-related quality of life. Correlative studies will evaluate exploratory biomarkers as potential predictive/prognostic factors. Assessments include clinical reviews and blood tests at baseline, then every 3-4 weeks; CT and bone scan at baseline, then every 12 weeks; 68Ga-PSMA-11 and 18F FDG PET/CTs at baseline; 68Ga-PSMA-11 PET/CT at week 24 and 177Lu-PSMA-617 SPECT/CT 24 hours after each 177Lu-PSMA-617 dose. Translational bloods include circulating tumour DNA and peripheral blood mononuclear cells collected at baseline, weeks 13 and 25, and at radiological progression. Optional fresh biopsies will be collected at baseline, weeks 3-5 and at progression. A sample size of 100 provides 90% power at the 10% level of significance to reject the null hypothesis (that 1 year PSA-PFS is 20%) if the alternative hypothesis is true (that 1 year PSA-PFS is 35%). Accrual as of the 11th of October 2022 is 23. Clinical trial information: NCT05150236 .