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)

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.

Status of PSMA-targeted radioligand therapy in prostate cancer: current data and future trials

“… 34 ENZA-p (NCT04419402) is an open-label phase II study randomizing 160 patients with mCRPC in a 1:1 ratio to either 177 Lu-PSMA-617 (up to four doses) with enzalutamide versus enzalutamide alone, with estimated study completion in June 2023. 35 This study also aims to identify possible predictive and prognostic biomarkers using circulating tumor cells (CTCs) and circulating tumor DNA. LuCAB (NCT05340374) is a phase I/II trial involving 44 patients with mCRPC to evaluate the combination of up to six cycles of 7.4 GBq of 177 Lu-PSMA-617 with cabazitaxel.…”

Pharmacological Optimization of PSMA-Based Radioligand Therapy

“…Similar results were found in a retrospective analysis of pre- and post-enzalutamide 68 Ga-PSMA-11 PET scans, with an increase of 49.6% in SUV max in target lesions after 13 ± 7 days of enzalutamide treatment [ 71 ]. A randomized phase II trial comparing enzalutamide alone with enzalutamide plus 177 Lu-PSMA-617 in patients with mCRPC, the so-called ENZA-p trial, is still pending [ 72 ]. The extent of PSMA upregulation may be time-dependent, with optimal expression after 9–14 days of treatment.…”

The real‐world outcomes of Lutetium‐177 PSMA‐617 radioligand therapy in metastatic castration‐resistant prostate cancer: Turkish Oncology Group multicenter study

“…However, it is uncertain whether this result is due to the synergistic effect of the combination therapy or because the former group received the Lu‐177 PSMA‐617 treatment earlier. The ENZA‐p trial and PSMAddition studies are expected to provide more clarity on this matter 13,14 …”

“…The ENZA-p trial and PSMAddition studies are expected to provide more clarity on this matter. 13,14 Follow up (months) In the TheraP trial, more than half of the participants experienced a decline of over 50% in their PSA levels, while in the VISION trial, this was the case for 46% of patients. 4 In our own cohort, we observed a similar trend, with 50.6% of patients achieving a PSA decline of over 50%.…”