Identifying lutetium-177 prostate-specific membrane antigen-617 treatment response patterns using a quantitative prostate-specific membrane antigen positron emission tomography/computed tomography traffic light workflow within the LuPIN trial

Abstract

Lutetium-177 prostate-specific membrane antigen-617 (¹⁷⁷Lu-PSMA-617) improves survival in metastatic castration-resistant prostate cancer, but more optimal tools are needed for therapeutic response assessment and early detection of resistance. We evaluated a quantitative imaging workflow using prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography to measure lesional changes following ¹⁷⁷Lu-PSMA-617 therapy. Pre- and post-treatment gallium-68-labeled PSMA-11 PET scans from the trial were analyzed using a novel traffic light workflow (TLW), assessing lesion-specific changes in tumor volume and maximum standardized uptake value in men treated with up to six cycles of ¹⁷⁷Lu-PSMA-617 and a radiation sensitizer (NOX66). Lesions were categorized as “reducing” (≥30%volume decrease), “stable” (<30% change), or “increasing” (≥30% increase or new lesions). Overall response was classified as “responder” (no increasing/new lesions), “low-volume progressor” (<50% of total tumor volume [TTV] increasing/new lesions), or “high-volume progressor” (>50% of TTV increasing/new lesions). TLW response classifications were compared with Response Evaluation Criteria in PSMA PET (RECIP) 1.0 and correlated with overall survival (OS). Among 37 men who underwent pre- and post-treatment PET imaging, 68% (25/37) completed six cycles, 32% (12/37) received 2-5 cycles, and 70% (26/37) had a >50% prostate-specific antigen (PSA) decline. The median PSA progression-free survival (PSA-PFS) was 8.6 months; median OS was 22.0 months. At post-treatment imaging, 54% (20/37) showed progression. TLW classified 24% as “responders,” 41% as “low-volume progressors,” and 35% as “high-volume progressors.” “Responders” had longer OS than “low-volume progressors” (median 17.7 vs. 12.0 months) or “high-volume progressors” (median 7.5 months, p=0.005). RECIP 1.0 classified 24% as partial response, 51% stable disease, and 24% as progressive disease. In summary, TLW shows potential to delineate complex response patterns. Following validation in larger cohorts, TLW will inform therapeutic decision-making.

Keywords

Metastatic prostate cancer / Theranostics / Lutetium-prostate-specific membrane antigen / Therapeutic response

References

[1] Hofman MS, Emmett L, Sandhu SK, et al. 177Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet. 2021; 397(10276):797-804. doi: 10.1016/S0140-6736(21)00237-3

[2] Sartor O, De Bono J, Chi KN, et al. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021; 385(12):1091-1103. doi: 10.1056/NEJMoa2107322

[3] Hofman MS, Violet J, Hicks RJ, et al. [ 177 Lu]-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; 19(6):825-833. doi: 10.1016/s1470-2045(18)30198-0

[4] Gafita A, Rauscher I, Weber M, et al. Novel framework for treatment response evaluation using PSMA PET/CT in patients with metastatic castration-resistant prostate cancer (RECIP 1.0): An international multicenter study. J Nucl Med. 2022; 63:1651-1658. doi: 10.2967/jnumed.121.263072

[5] Grubmuller B, Senn D, Kramer G, et al. Response assessment using 68Ga-PSMA ligand PET in patients undergoing 177Lu-PSMA radioligand therapy for metastatic castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging. 2019; 46(5):1063-1072. doi: 10.1007/s00259-018-4236-4

[6] Crumbaker M, Pathmanandavel S, Yam AO, et al. Phase I/II trial of the combination of 177lutetium prostate specific membrane antigen 617 and idronoxil (NOX66) in men with end-stage metastatic castration-resistant prostate cancer (LuPIN). Eur Urol Oncol. 2020; 4:963-970. doi: 10.1016/j.euo.2020.07.002

[7] Young H, Baum R, Cremerius U, et al. Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European organization for research and treatment of cancer

[8] ( EORTC) PET study group. Eur J Cancer. 1999; 35(13):1773-1782. do i: 10.1016/S0959-8049(99 ) 00229-4

[9] Jansen BHE, Cysouw MCF, Vis AN, et al. Repeatability of quantitative 18F-DCFPyL PET/CT measurements in metastatic prostate cancer. J Nucl Med. 2020; 61(9):1320-1325. do i: 10.2967/jnumed.119.236075

[10] Scher HI, Morris MJ, Stadler WM, et al. Trial design and objectives for castration-resistant prostate cancer: Updated recommendations from the prostate cancer clinical trials working group 3. J Clin Oncol. 2016; 34(12):1402-1418. do i: 10.1200/JCO.2015.64.2702

[11] Pathmanandavel S, Crumbaker M, Yam AO, et al. 177Lu-PSMA-617 and idronoxil in men with end-stage metastatic castration-resistant prostate cancer (LuPIN): Patient outcomes and predictors of treatment response in a phase I/II trial. J Nucl Med. 2022; 63(4):560-566. doi: 10.2967/jnumed.121.262552

[12] Fanti S, Goffin K, Hadaschik BA, et al. Consensus statements on PSMA PET/CT response assessment criteria in prostate cancer. Eur J Nucl Med Mol Imaging. 2020; 48:469-476. do i: 10.1007/s00259-020-04934-4

[13] Pollard JH, Raman C, Zakharia Y, et al. Quantitative test-retest measurement of 68Ga-PSMA-HBED-CC in tumor and normal tissue. J Nucl Med. 2020; 61(8):1145-1152. doi: 10.2967/jnumed.119.236083

[14] Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45(2):228-247. do i: 10.1016/j.ejca.2008.10.026

[15] De Wreede LC, Fiocco M, Putter H. Mstate: An R package for the analysis of competing risks and multi-state models. J Stat Softw. 2011; 38(7):1-30. doi: 10.18637/jss.v038.i07

[16] Stoffel MA, Nakagawa S, Schielzeth H, Goslee S. Rptr: Repeatability estimation and variance decomposition by generalized linear mixed‐effects models. Methods Ecol Evol. 2017; 8(11):1639-1644. doi: 10.1111/2041-210x.12797

[17] Team RC. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing. Last accessed on 2023 Oct 17].

[18] Pathmanandavel S, Crumbaker M, Nguyen A, et al. The prognostic value of posttreatment 68Ga-PSMA-11 PET/CT and 18F-FDG PET/CT in metastatic castration-resistant prostate cancer treated with 177Lu-PSMA-617 and NOX66 in a phase I/II trial (LuPIN). J Nucl Med. 2022; 64:69-74. doi: 10.2967/jnumed.122.264104

[19] Andrei G, Wolfgang W, Robert T, Matthias E. Predictive value of interim PSMA PET during 177Lu-PSMA radioligand therapy for overall survival in patients with advanced prostate cancer. J Nuclear Med. 2019; 60(supplement 1):73.

[20] Heinzel A, Boghos D, Mottaghy FM, et al. 68Ga-PSMA PET/CT for monitoring response to 177Lu-PSMA-617 radioligand therapy in patients with metastatic castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging. 2019; 46(5):1054-1062. doi: 10.1007/s00259-019-4258-6

[21] Gafita A, Calais J, Grogan TR, et al. Nomograms to predict outcomes after 177Lu-PSMA therapy in men with metastatic castration-resistant prostate cancer: An international, multicentre, retrospective study. Lancet Oncol. 2021; 22:1115-1125. doi: 10.1016/s1470-2045(21)00274-6

[22] Kuo PH, Morris MJ, Hesterman J, et al. Quantitative 68Ga-PSMA-11 PET and clinical outcomes in metastatic castration-resistant prostate cancer following 177Lu-PSMA-617 (VISION trial). Radiology. 2024; 312(2):e233460. doi: 10.1148/radiol.233460

[23] Current K, Meyer C, Magyar CE, et al. Investigating PSMA-targeted radioligand therapy efficacy as a function of cellular PSMA levels and intratumoral PSMA heterogeneity. Clin Cancer Res. 2020; 26(12):2946-2955. doi: 10.1158/1078-0432.CCR-19-1485

[24] Paschalis A, Sheehan B, Riisnaes R, et al. Prostate-specific membrane antigen heterogeneity and DNA repair defects in prostate cancer. Eur Urol. 2019; 76(4):469-478. doi: 10.1016/j.eururo.2019.06.030

[25] Beltran H, Hruszkewycz A, Scher HI, et al. The role of lineage plasticity in prostate cancer therapy resistance. Clin Cancer Res. 2019; 25(23):6916-6924. doi: 10.1158/1078-0432.CCR-19-1423

[26] Matuszczak M, Salagierski M. Oligometastatic disease in prostate cancer. Evolving paradigm: Current knowledge, diagnostic techniques and treatment strategies. Arch Med Sci. 2022. doi: 10.5114/aoms/156170

[27] Pepe P, Pepe L, Curduman M, Pennisi M, Fraggetta F. Ductal prostate cancer staging: Role of PSMA PET/CT. Arch Ital Urol Androl. 2024; 96(1):12132. doi: 10.4081/aiua.2024.12132

[28] Emmett L, Subramaniam S, Crumbaker M, et al. [ 177Lu] Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): An open-label, multicentre, randomised, phase 2 trial. Lancet Oncol. 2024; 25(5):563-571. doi: 10.1016/s1470-2045(24)00135-9

[29] Feuerecker B, Tauber R, Knorr K, et al. Activity and adverse events of actinium-225-PSMA-617 in advanced metastatic castration-resistant prostate cancer after failure of lutetium-177- PSMA. Eur Urol. 2021; 79(3):343-350. doi: 10.1016/j.eururo.2020.11.013

[30] Sathekge MM, Bruchertseifer F, Vorster M, Morgenstern A, Lawal IO. Global experience with PSMA-based alpha therapy in prostate cancer. Eur J Nucl Med Mol Imaging. 2021; 49(1):30-46. doi: 10.1007/s00259-021-05434-9

[31] Sathekge MM, Lawal IO, Bal C, et al. Actinium-225-PSMA radioligand therapy of metastatic castration-resistant prostate cancer (WARMTH Act): A multicentre, retrospective study. Lancet Oncol. 2024; 25(2):175-183. doi: 10.1016/S1470-2045(23)00638-1

[32] Sartor O, Ledet E, Huang M, et al. Prediction of resistance to 177Lu-PSMA therapy by assessment of baseline circulating tumor DNA biomarkers. J Nucl Med. 2023; 64(11):1721-1725. do i: 10.2967/jnumed.123.266167

[33] John N, Pathmanandavel S, Crumbaker M, et al. 177Lu-PSMA SPECT quantitation at 6 weeks (Dose 2) predicts short progression-free survival for patients undergoing ¹⁷⁷Lu-PSMA-I&T therapy. J Nucl Med. 2023; 64(3):410-415. doi: 10.2967/jnumed.122.264677

[34] Neubauer MC, Nicolas GP, Bauman A, et al. Early response monitoring during [¹⁷⁷Lu]Lu-PSMA I&T therapy with quantitated SPECT/CT predicts overall survival of mCRPC patients: Subgroup analysis of a swiss-wide prospective registry study. Eur J Nucl Med Mol Imaging. 2024; 51(4):1185-1193. doi: 10.1007/s00259-023-06536-2