Elsevier

The Lancet Oncology

Volume 19, Issue 6, June 2018, Pages 825-833
The Lancet Oncology

Articles
[177Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study

https://doi.org/10.1016/S1470-2045(18)30198-0Get rights and content

Summary

Background

Progressive metastatic castration-resistant prostate cancer is a highly lethal disorder and new effective therapeutic agents that improve patient outcomes are urgently needed. Lutetium-177 [177Lu]-PSMA-617, a radiolabelled small molecule, binds with high affinity to prostate-specific membrane antigen (PSMA) enabling beta particle therapy targeted to metastatic castration-resistant prostate cancer. We aimed to investigate the safety, efficacy, and effect on quality of life of [177Lu]-PSMA-617 in men with metastatic castration-resistant prostate cancer who progressed after standard treatments.

Methods

In this single-arm, single-centre, phase 2 trial, we recruited men (aged 18 years and older) with metastatic castration-resistant prostate cancer and progressive disease after standard treatments, including taxane-based chemotherapy and second-generation anti-androgens, from the Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Patients underwent a screening PSMA and FDG-PET/CT to confirm high PSMA-expression. Eligible patients had progressive disease defined by imaging (according to Response Evaluation Criteria In Solid Tumours [RECIST] or bone scan) or new pain in an area of radiographically evident disease, and were required to have an Eastern Cooperative Oncology Group (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 endpoint was PSA response according to Prostate Cancer Clinical Trial Working Group criteria defined as a greater than 50% PSA decline from baseline and toxicity according to CTCAE. Additional primary endpoints were imaging responses (as measured by bone scan, CT, PSMA, and FDG PET/CT) and quality of life (assessed with the EORTC-Q30 and Brief Pain Inventory-Short Form questionnaires), all measured up to 3 months post completion of treatment. This trial is registered with the Australian New Zealand Clinical Trials Registry, number 12615000912583.

Findings

Between Aug 26, 2015, and Dec 8, 2016, 43 men were screened to identify 30 patients eligible for treatment. 26 (87%) had received at least one line of previous chemotherapy (80% docetaxel and 47% cabazitaxel) and 25 (83%) received prior abiraterone acetate, enzalutamide, or both. The mean administered radioactivity was 7·5 GBq per cycle. 17 (57%) of 30 patients (95% CI 37–75) achieved a PSA decline of 50% or more. There were no treatment-related deaths. The most common toxic effects related to [177Lu]-PSMA-617 were grade 1 dry mouth recorded in 26 (87%) patients, grade 1 and 2 transient nausea in 15 (50%), and G1–2 fatigue in 15 (50%). Grade 3 or 4 thrombocytopenia possibly attributed to [177Lu]-PSMA-617 occurred in four (13%) patients. Objective response in nodal or visceral disease was reported in 14 (82%) of 17 patients with measurable disease. Clinically meaningful improvements in pain severity and interference scores were recorded at all timepoints. 11 (37%) patients experienced a ten point or more improvement in global health score by the second cycle of treatment.

Interpretation

Our findings show that radionuclide treatment with [177Lu]-PSMA-617 has high response rates, low toxic effects, and reduction of pain in men with metastatic castration-resistant prostate cancer who have progressed after conventional treatments. This evidence supports the need for randomised controlled trials to further assess efficacy compared with current standards of care.

Funding

None.

Introduction

Prostate cancer is the second most common cancer and the fifth leading cause of death from cancer worldwide.1 Since the approval of docetaxel as first-line chemotherapy in 2004, several new life-prolonging systemic treatments have been introduced for metastatic, castration-resistant prostate cancer including abiraterone, enzalutamide, cabazitaxel, and radium-223.2, 3, 4, 5 However, all patients subsequently progress and there is an urgent need for effective therapeutic agents that can improve patient outcome including ameliorating disease-related symptoms and improving quality of life in the terminal stages of disease.6

Research in context

Evidence before this study

We searched PubMed and MEDLINE for peer-reviewed, original studies published in English up to the commencement of our trial design in July, 2015, with the search terms “Lu-177-PSMA”, “Lutetium”, “radioligand treatment”, and “PSMA”. We also reviewed key journals and congress abstracts in the fields of nuclear medicine and urological oncology. We found small retrospective case reports or series suggesting high activity in patients given treatment on a compassionate basis after failing conventional treatments. No prospective data for radionuclide treatment with [177Lu]-labelled PSMA were available. Therefore, we designed a phase 2 prospective trial to investigate the efficacy, safety, and effect on quality of life of this treatment. Several retrospective studies have been published since, but high-quality, prospectively collected data on outcomes and safety are still unavailable.

Added value of this study

This is the first prospective phase 2 study to provide compelling evidence that radionuclide treatment with [177Lu]-PSMA-617 has promising anti-tumour activity, a favourable toxicity profile, and improves quality of life in men with metastatic castration-resistant prostate cancer who have progressed after standard treatments including chemotherapy and second-generation anti-androgens.

Implications of all the available evidence

Collective data from this phase 2 study and several retrospective series, provides proof of concept that [177Lu]-PSMA-617 has promising anti-tumour activity, low toxicity, and improves quality of life in patients with metastatic castration-resistant prostate cancer who have not responded to most conventional treatments and exhibit high PSMA expression on PSMA PET/CT. In view of the almost ubiquitous nature of PSMA expression in most metastatic castration-resistant prostate cancers, [177Lu]-PSMA-617 offers a potential additional treatment option for men with metastatic castration-resistant prostate cancer. Studies comparing [177Lu]-PSMA-617 to existing standards of care, or in combination with other treatments are now required. The evidence from this study formed the basis of a recently commenced Australian multicentre randomised phase 2 trial comparing [177Lu]-PSMA-617 to cabazitaxel (NCT03392428), and several early phase trials combining [177Lu]-PSMA-617 with other new treatments.

Lutetium-177 [177Lu]-PSMA-617 (LuPSMA), is a small molecule inhibitor that binds with high affinity to prostate-specific membrane antigen (PSMA). The short-range 1 mm path length of the beta-particle emitted by 177Lu enables effective delivery of radiation to tumours while minimising damage to surrounding normal tissues. PSMA, also known as folate hydrolase I, is a transmembrane glycoprotein overexpressed 100 to 1000 times in prostate cancers, with expression further increased in metastatic and castration-resistant carcinomas.7 LuPSMA is a variant of [68Ga]-PSMA-11 used for PET imaging that has been optimised for therapeutic use. LuPSMA was developed by the German Cancer Research Center (DKFZ, Deutsches Krebsforschungszentrum) in collaboration with University Hospital Heidelberg.8 LuPSMA is distinct from antibodies such as J5919 showing more rapid plasma clearance and higher affinity binding to PSMA. Several retrospective studies10, 11, 12, 13, 14, 15, 16, 17 of LuPSMA have reported favourable biochemical and imaging responses as well as significant pain relief in the patients treated.

In this prospective, phase 2 trial, we aimed to investigate the efficacy, safety, and effect on quality of life of LuPSMA in men with progressive metastatic castration-resistant prostate cancer who had failed standard therapies.

Section snippets

Study design and participants

For this investigator-initiated, single-institution phase 2 trial, eligibility criteria included pathologically (adenocarcinoma) confirmed metastatic castration-resistant prostate cancer with progressive disease after standard treatments, including taxane-based chemotherapy and second-generation anti-androgen treatment (abiraterone, enzalutamide, or both), unless patients were medically unsuitable for or refused these standard treatments. Progressive disease for trial entry was defined by

Results

Between Aug 26, 2015, and Dec 8, 2016, 43 patients were screened to identify 30 patients who met the eligibility criteria (figure 1). The first LuPSMA treatment was administered on Oct 22, 2015, and the last cycle administered on May 18, 2017. The data cutoff for follow-up was Nov 9, 2017. Seven (16%) patients were excluded as PET/CT showed either low PSMA-avidity or FDG-discordant disease (appendix p 1). Baseline characteristics of the cohort are summarised in table 1 and individual patient

Discussion

In this phase 2 study using PSMA theranostics to deliver personalised LuPSMA treatment in a poor prognostic cohort of men with metastatic castration-resistant prostate cancer who progressed after standard treatments, we recorded a 50% or higher PSA response of 57%. Additionally, we recorded rapid and clinically meaningful improvements in quality of life. Overall, LuPSMA treatment was well tolerated with predominantly G1 treatment-related toxicities that were largely self-limiting and easily

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