Nomograms to predict outcomes after 177Lu-PSMA therapy in men with metastatic castration-resistant prostate cancer: an international, multicentre, retrospective study

Abstract

Background: Lutetium-177 (177Lu) prostate-specific membrane antigen (177Lu-PSMA) is a novel targeted treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). Predictors of outcomes after 177Lu-PSMA to enhance its clinical implementation are yet to be identified. We aimed to develop nomograms to predict outcomes after 177Lu-PSMA in patients with mCRPC.

Methods: In this multicentre, retrospective study, we screened patients with mCRPC who had received 177Lu-PSMA between Dec 10, 2014, and July 19, 2019, as part of the previous phase 2 trials (NCT03042312, ACTRN12615000912583) or compassionate access programmes at six hospitals and academic centres in Germany, the USA, and Australia. Eligible patients had received intravenous 6·0-8·5 GBq 177Lu-PSMA once every 6-8 weeks, for a maximum of four to six cycles, and had available baseline [68Ga]Ga-PSMA-11 PET/CT scan, clinical data, and survival outcomes. Putative predictors included 18 pretherapeutic clinicopathological and [68Ga]Ga-PSMA-11 PET/CT variables. Data were collected locally and centralised. Primary outcomes for the nomograms were overall survival and prostate-specific antigen (PSA)-progression-free survival. Nomograms for each outcome were computed from Cox regression models with LASSO penalty for variable selection. Model performance was measured by examining discrimination (Harrell's C-index), calibration (calibration plots), and utility (patient stratification into low-risk vs high-risk groups). Models were validated internally using bootstrapping and externally by calculating their performance on a validation cohort.

Findings: Between April 23, 2019, and Jan 13, 2020, 414 patients were screened; 270 (65%) of whom were eligible and were divided into development (n=196) and validation (n=74) cohorts. The median duration of follow-up was 21·5 months (IQR 13·3-30·7). Predictors included in the nomograms were time since initial diagnosis of prostate cancer, chemotherapy status, baseline haemoglobin concentration, and [68Ga]Ga-PSMA-11 PET/CT parameters (molecular imaging TNM classification and tumour burden). The C-index of the overall survival model was 0·71 (95% CI 0·69-0·73). Similar C-indices were achieved at internal validation (0·71 [0·69-0·73]) and external validation (0·72 [0·68-0·76]). The C-index of the PSA-progression-free survival model was 0·70 (95% CI 0·68-0·72). Similar C-indices were achieved at internal validation (0·70 [0·68-0·72]) and external validation (0·71 [0·68-0·74]). Both models were adequately calibrated and their predictions correlated with the observed outcome. Compared with high-risk patients, low-risk patients had significantly longer overall survival in the validation cohort (24·9 months [95% CI 16·8-27·3] vs 7·4 months [4·0-10·8]; p<0·0001) and PSA-progression-free survival (6·6 months [6·0-7·1] vs 2·5 months [1·2-3·8]; p=0·022).

Interpretation: These externally validated nomograms that are predictive of outcomes after 177Lu-PSMA in patients with mCRPC might help in clinical trial design and individual clinical decision making, particularly at institutions where 177Lu-PSMA is introduced as a novel therapeutic option.

Funding: Prostate Cancer Foundation.

Conflict of interest statement

Declaration of interests JCa reports previous consulting activities for Curium Pharma, GE Healthcare, Janssen Pharmaceuticals, and Point Biopharma, outside of the submitted work. BH reports personal fees from ABX, Bayer, Lightpoint Medical, Janssen, Bristol-Myers Squibb, and Astellas and travel fees from AstraZeneca, Janssen, and Astellas, outside of the submitted work. KH reports personal fees from Bayer, SIRTEX, Adacap, Curium, Endocyte, IPSEN, Siemens Healthineers, GE Healthcare, Amgen, Novartis, Y-mAbs, Bain Capital, and MBM Capital; personal fees and non-financial support from Sofie Biosciences; non-financial support from ABX; and grants and personal fees from BTG, outside the submitted work. JCz is a founder, board member, and holds equity in Sofie Biosciences and Trethera Therapeutics (intellectual property is patented by the University of California and licensed to Sofie Biosciences and Trethera Therapeutics); and was a consultant for Endocyte (VISION trial steering committee), Actinium Pharmaceuticals, and Point Biopharma, outside of the submitted work. MSH reports personal fees from Janssen (lecture honorarium), Mundipharma (lecture honorarium), Astellas (lecture honorarium), AstraZeneca (lecture honorarium), and MSD (advisory forum); and research support from Endocyte, AAA, and Novartis, outside of the submitted work. WPF has been a consultant for Endocyte and BTG, and has received fees from RadioMedix and Bayer, outside of the submitted work. ME reports previous consulting activities for Blue Earth Diagnostics, Progenics Pharmaceuticals, and Point Biopharma, and a patent application for rhPSMA, outside of the submitted work. All other authors declare no competing interests.

Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY NC ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.