TY - JOUR
T1 - [ 177 Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial)
T2 - a single-centre, single-arm, phase 2 study
AU - Hofman, Michael S.
AU - Violet, John
AU - Hicks, Rodney J.
AU - Ferdinandus, Justin
AU - Ping Thang, Sue
AU - Akhurst, Tim
AU - Iravani, Amir
AU - Kong, Grace
AU - Ravi Kumar, Aravind
AU - Murphy, Declan G.
AU - Eu, Peter
AU - Jackson, Price
AU - Scalzo, Mark
AU - Williams, Scott G.
AU - Sandhu, Shahneen
N1 - Funding Information:
There was no direct funding source for the study. 177 Lu (no carrier added) was supplied by the Australian Nuclear Science and Technology Organisation (ANSTO, Sydney, Australia) and PSMA-617 by Advanced Biochemical Compounds (ABX, Radeberg, Germany). Neither had any role in study design, data collection, data analysis and interpretation, or writing of the report. The study was sponsored by the Peter MacCallum Cancer Centre (Melbourne, Australia). All authors had full access to all of the data. The corresponding author takes final responsibility for the analysis and decision to submit for publication.
Funding Information:
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 managed. Our results are broadly consistent with retrospective reports published to date. 10–17 Collectively, these data suggest that LuPSMA is a useful therapeutic option for patients with metastatic castration-resistant prostate cancer and additional studies are warranted to understand how to position this new treatment in the evolving treatment paradigm for metastatic castration-resistant prostate cancer. The highly targeted nature of 177 Lu with a short-range beta particle limits effects on normal tissue, except for sites of physiological PSMA expression including salivary and lacrimal glands. LuPSMA was well tolerated with no dose-limiting toxicities seen. We observed grade 1 xerostomia in most patients, which is higher than previously reported, possibly attributed to specific questioning of this potential toxicity within a prospective trial setting. The occurrence of treatment-related grade 3–4 haematological toxicity was low and comparable to the largest retrospective cohort published to date. 11 Notably, all patients with grade 3–4 treatment-related toxicity had baseline thrombocytopenia or anaemia due to a combination of reduced marrow reserve after previous chemotherapy or marrow infiltration. Given the lack of PSMA-expression in normal bone marrow, 28 the haematoxicity arising from LuPSMA is probably the result of damage to adjacent marrow in patients with extensive osseous disease. Overall, however, owing to the rapid plasma clearance of the small-molecule ligand, haematoxicity appears substantially lower than with the [ 177 Lu]-J591 antibody. 9 LuPSMA theranostics enable a highly personalised approach using PSMA PET/CT to non-invasively image and quantitate PSMA expression to select patients most likely to benefit from treatment. In this study, we additionally excluded patients if they had sites of low or absent PSMA expression demonstrating high FDG-avidity. We also ceased administering further cycles of treatment if there was no or low uptake on post-treatment imaging indicative of an exceptional response. This treatment paradigm applied in our protocol has evolved from our experience using peptide receptor radionuclide therapy for the treatment of metastatic neuroendocrine tumours (NETs). The principals and expertise required here broadly parallel those using [ 68 Ga]-DOTATATE PET/CT and [ 177 Lu]-DOTATATE in NET. 29 The optimal number of LuPSMA cycles was, however, not determined in this study and administration of additional cycles could be clinically beneficial, especially given the low toxicity observed. Further research is also needed to define the proportion of patients who progress with PSMA-positive or PSMA-negative disease. Improving quality of life and avoiding detrimental effects of treatment are important considerations for patients with metastatic castration-resistant prostate cancer, many of whom are already symptomatic from their disease. LuPSMA appears particularly effective for pain palliation with rapid relief of pain observed in many patients. For 27 patients with pain at baseline, this improved in 37% after the first cycle of treatment. This effect appears to be better than other agents such as cabazitaxel, with only 9% of patients experiencing pain relief in the TROPIC trial. 4 The greater than 50% PSA response of 57% in this study is encouraging, particularly when compared with established agents (eg, a response of 39% was observed after treatment with cabazitaxel). 4 76% of patients had a PSA response greater than 30% compared to 16% in the Ra-223 ALSYMPCA study 3 highlighting the advantage of a tumour-targeted compound compared with an exclusively bone-seeking agent. The PSA progression-free survival of 7 months noted in this study is similar to that noted in the cabazitaxel TROPIC trial 4 and longer than the 3·6 months recorded with Ra-223. 3 Our results must be interpreted in the context of a heavily pre-treated patient cohort who had exhausted most standard therapies, including cabazitaxel in almost 50%, and had a declining performance status. Indeed, any sustained response to further treatment in this setting is promising, especially if the treatment improves quality of life without significant toxic effects. Nevertheless, without a control group, our results must be interpreted with caution. Additionally, we selected patients based on a predefined imaging phenotype that might have excluded patients with an especially unfavourable prognosis. Our data suggest that LuPSMA could represent a new life-prolonging treatment for men with metastatic castration-resistant prostate cancer, and randomised trials comparing LuPSMA with existing standards of care are now needed. The results of multi-modality imaging can be summarised as demonstrating remarkable responses in nodal and visceral disease, but a pattern of ultimate progression in new sites of osseous disease or marrow infiltration. We postulate that 177 Lu is less effective in targeting microscopic deposits of marrow disease, below the limits of detection on baseline PSMA PET imaging, but that subsequently progress. Future analysis of the voxel-based dosimetric data collected in this cohort to quantify radiation delivered to tumour and normal lesions could enable optimisation of 177 Lu administered activities and establish the safety of administering more than four cycles of LuPSMA. PSMA-617 radiolabelled to alpha-emitters such as actinium-225, 30 or combining LuPSMA with other treatments, such as chemotherapy, poly(ADP-ribose) polymerase inhibitors, or anti-programmed death ligand might also be feasible and warrant investigation. Although the current study focuses on a heavily pre-treated population of metastatic castration-resistant prostate cancer patients with terminal disease, the safety and efficacy of this treatment earlier in the therapeutic paradigm might also be worth assessing, perhaps even before the emergence of castration-resistance. In conclusion, we show in a prospective study that in men with metastatic castration-resistant prostate cancer who have progressed after standard treatments with PSMA-avid disease, LuPSMA resulted in high responses, a low toxicity profile, and improves quality-of-life parameters especially in men with pain. Based on this promising data, we have commenced a multicentre randomised trial comparing LuPSMA with cabazitaxel chemotherapy ( NCT03392428 ). Contributors MSH, JV, RJH, SGW, and SS designed the study. MSH, JV, SS, SPT, and JF collected data. MSH, JV, and JF analysed data. MSH, JV, SS, SGW, and RJH interpreted data. MSH, JV, SGW, TA, AI, GK, ARK, DGM, RJH, and SS were responsible for the accrual of patients. PE had oversight of radiopharmaceutical protocol and manufacture, MS was the co-ordinating nuclear medicine technologist, and PJ performed dosimetry analysis. MSH presented interim study findings at a major congress (2017 ESMO congress, abstract 785O); and all authors contributed to the writing and approval of this report. Declaration of interests MSH reports personal fees for honoraria from Ipsen Australia, Sanofi Genzyme, and Endocyte, all outside of the submitted work. JV reports personal fees for Honoraria from Janssen Australia, outside of the submitted work. All other authors declare no competing interests. Acknowledgments This study was sponsored by the Peter MacCallum Cancer Centre (Melbourne, VIC, Australia). 177 Lu (no carrier added) was supplied by the Australian Nuclear Science and Technology Organisation (ANSTO, Sydney, Australia) and PSMA-617 by Advanced Biochemical Compounds (ABX, Radeberg, Germany). MSH is supported by a Clinical Fellowship Award from the Peter MacCallum Foundation and a Movember Clinical Trials Award awarded through the Prostate Cancer Foundation of Australia's Research Program. SS is supported by a Clinical Fellowship Award from the Peter MacCallum Foundation and by the John Mills Young Investigator Award from Prostate Cancer Foundation of Australia. RJH is supported by a National Health and Medical Research Foundation of Australia Practitioner Fellowship. We thank the nuclear medicine and nursing staff at the Peter MacCallum Cancer Centre and all the patients who agreed to participate in the study. We also thank Mathias Bressel (biostatistican) for analysis of the quality-of-life data.
Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/6
Y1 - 2018/6
N2 - 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 [ 177 Lu]-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 [ 177 Lu]-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 [ 177 Lu]-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 [ 177 Lu]-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 [ 177 Lu]-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 [ 177 Lu]-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.
AB - 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 [ 177 Lu]-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 [ 177 Lu]-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 [ 177 Lu]-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 [ 177 Lu]-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 [ 177 Lu]-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 [ 177 Lu]-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.
UR - http://www.scopus.com/inward/record.url?scp=85046797112&partnerID=8YFLogxK
U2 - 10.1016/S1470-2045(18)30198-0
DO - 10.1016/S1470-2045(18)30198-0
M3 - Article
C2 - 29752180
AN - SCOPUS:85046797112
SN - 1470-2045
VL - 19
SP - 825
EP - 833
JO - The Lancet Oncology
JF - The Lancet Oncology
IS - 6
ER -