Evolution: Phase II study of radionuclide ¹⁷⁷Lu-PSMA-617 therapy versus ¹⁷⁷Lu-PSMA-617 in combination with ipilimumab and nivolumab for men with metastatic castration-resistant prostate cancer (mCRPC; ANZUP 2001).

Abstract

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 .

Metastatic castration-resistant prostate cancer and immune checkpoint inhibitors

“…Первичная конечная точка -12-месячная ВБП по уровню ПСА. Продолжаются трансляционные исследования, изучающие влияние микроокружения опухоли и предикторов ответа на эту комбинированную терапию [35]. В настоящее время проводятся дополнительные доклинические исследования, изучающие полезность актиния в дополнение к ИИКТ [36].…”

Clinical Management of Advanced Prostate Cancer: Where Does Radiopharmaceutical Therapy Fit in the Treatment Algorithm?

“…On the basis of prior evidence of enhanced PARP inhibitor activity when combined with radiotherapy, the phase I LuPARP trial is studying the safety of combination olaparib and 177 Lu-PSMA-617 (60). Numerous studies are assessing the safety and efficacy of combination immunotherapy and 177 Lu-PSMA-617 in hopes of improving on the limited single-agent efficacy of immune checkpoint inhibitors in mCRPC to date (61,62).…”

Metastatic Castration-Resistant Prostate Cancer, Immune Checkpoint Inhibitors, and Beyond

“…The primary endpoint is 12-month PSA progression-free survival. There are ongoing translational studies looking into the tumor microenvironment effects and predictors of response to this combination therapy [ 35 ]. There are further preclinical studies investigating the utility of actinium in addition to ICIs that are currently underway [ 36 ].…”