ASCO 2018: Lutetium-177 PSMA-617 Theranostics in mCRPC: Interim Results of a Phase II Trial

Chicago, IL (UroToday.com)  Lutetium-177 (177Lu)-PSMA617 is a radiolabeled small molecule that binds with high affinity to prostate specific membrane antigen (PSMA) enabling tumor-targeted delivery of beta-radiation. Progressive mCRPC is a highly lethal disorder and new effective agents that improve quantity and quality of life are urgently needed. In a recent study published in Lancet Oncology, Hofman et al. reported initial results of a single-centre phase II trial assessing [177Lu]-PSMA-617 in 30 heavily pretreated mCRPC patients [1]. 

Among these men, 87% had received at least one line of previous chemotherapy and 83% received prior abiraterone acetate, enzalutamide, or both. There were 17 (57%) men who achieved a PSA decline of 50% or more, and there were no treatment-related deaths. Grade 3 or 4 thrombocytopenia potentially attributed to [177Lu]-PSMA-617 occurred in four (13%) patients. Furthermore, objective response in nodal/visceral disease occurred in 14 (82%) of 17 patients with measurable disease, and clinically meaningful improvements in pain severity occurred at all time points. Based on these results, this cohort has been expanded, and at ASCO 2018 annual meeting, Dr. Sandhu and colleagues presented updated results of the expansion cohort for the [177Lu]-PSMA-617 phase II trial. 

Prior to enrollment for this study, patients underwent a screening PSMA and FDG-PET/CT to confirm high PSMA-expression. Eligible patients had progressive disease defined by imaging (according to RECIST or bone scan) or new pain in an area of radiographically evident disease, mCRPC, and were required to have an ECOG performance status score of 2 or lower. Eligible patients received up to four cycles of intravenous [177Lu]-PSMA-617, at six weekly intervals. The primary endpoints were 50% PSA response rate (PCWG2) and toxicity (CTCAE v4.3). The secondary endpoints were objective response rate (ORR), quality of life (EORTC QLQ-C30, BPI), PSA progression free survival (PFS) and overall survival (OS). 

There were 50 patients that comprised this analysis, with a median age of 71 years (range: 50-87). Among these men, 90% had progressed after abiraterone and/or enzalutamide, and 88% progressed after chemotherapy (84% post docetaxel and 48% following docetaxel and cabazitaxel). A median of 4 (range: 1-4) cycles and mean radioactivity of 7.5 GBq/cycle (range 4.0-8.9) was administered. At this analysis, the primary endpoint of PSA decline ≥ 50% was achieved in 31 of 50 patients (62%), including 22 patients (44%) with a PSA decline ≥ 80%. Median PSA PFS was 7.0 months (95%CI 5.7-8.8) and median OS was 12.5 months (95%CI 10.0-18.7). Common grade 1-2 toxicities included dry mouth (68%), fatigue (38%), nausea (48%) and pain flare (10%). Grade 3-4 hematological toxicities attributed as possibly related to [177Lu]-PSMA-617 included thrombocytopenia (10%), anemia (10%), and neutropenia (6%).  

This [177Lu]-PSMA-617 phase II trial provides encouraging results for patients with mCRPC that have few (if any) additional treatment options. These results, coupled with seminal work in this disease space from Germany [2], will be important as these trials continue to accrue patients with longer term outcomes. Dr. Sandhu concluded noting that these results with [177Lu]-PSMA-617 suggest high response rates and low toxicity in men with mCRPC who progressed after multiple conventional therapies. Excitingly, results from this phase II trial have resulted in opening a randomized trial comparing [177Lu]-PSMA-617 to cabazitaxel.  

Presented By: Shahneen K. Sandhu, Department of Medical Oncology, Peter MacCallum Cancer Centre, Australia, Melbourne, Australia 
Co-Authors: John A Violet, Justin Ferdinandus, Sue-Ping Thang, Amir Iravani, Christina Guo, Grace Kong, Aravind Ravi Kumar, Timothy J. Akhurst, Alexis Beaulieu, Declan G. Murphy, Jennifer Mooi, Ben Tran, Guy C. Toner, Scott Williams, Rodney J Hicks, Michael Hofman; Department of Medical Oncology, Peter MacCallum Cancer Centre, Australia, Melbourne, Australia; Department of Radiation Oncology, Peter MacCallum Cancer Centre, Australia, Melbourne, Australia; Department of Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Australia; Department of Cancer Imaging, Peter MacCallum Cancer Centre, Australia, Melbourne, Australia; Department of Medical Oncology, Peter MacCallum Cancer Centre, Australia, Melboune, Australia; Department of Cancer Surgery, Peter MacCallum Cancer Centre, Australia, Melbourne Victoria, AU; Department of Medical Oncology, Peter MacCallum Cancer Centre, Australia, Victoria, Australia 

Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md  at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA

References: 
1. Hofman MS, Violet J, Hicks RJ, et al. [177Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): A single-centre, single-arm, phase 2 study. Lancet Oncol 2018 May 7 [Epub ahead of print]. 
2. Kletting P, Schuchardt C, Kulkarni HR, et al. Investigating the effect of ligand amount and injected therapeutic activity: A simulation study for 177Lu-labeled PSMA-targeting peptides. PLoS One 2016;11(9):e0162303.
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