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. MethodsIn 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.

Enzalutamide Enhances PSMA Expression of PSMA-Low Prostate Cancer

“…Our results demonstrate that enzalutamide increases PSMA expression significantly in all three cell lines already after one week of treatment. 22Rv1 expresses low levels of PSMA which was confirmed by immunohistochemistry and flow cytometry and therefore closely represents challenging patient cohorts that will potentially not be eligible for or respond to RLT, as demonstrated in a recent multi-center analysis of clinical predictors of non-response [9]. This finding provided the rationale for investigating the effect of ARB with enzalutamide on PSMA expression in vivo using PSMA-low 22Rv1 tumors.…”

“…PSMA, a transmembrane glycoprotein overexpressed on PC cells, has emerged as a novel target for imaging and therapy of PC. High PSMA expression levels are associated with enhanced tumor targeting by RLT and low or heterogeneous PSMA expression represents a resistance mechanism to RLT [9,17,18]. Focal uptake on PSMA PET is a prerequisite for RLT eligibility.…”

“…Pre-treatment with ARB might thus render patients with PSMAlow PC eligible for RLT. Although the mechanisms underlying lack of responsiveness to RLT are very complex and still under investigation, PSMA expression has been identified as a strong predictor of RLT response and long survival [9,17]. Therefore, the impact of enzalutamide on PSMA expression as well as RLT eligibility and efficacy should further be assessed in prospective clinical trials.…”

“…Radioligand therapy (RLT) targeting the prostate-specific membrane antigen (PSMA) is a new therapeutic option for CRPC patients [5][6][7]. In the phase 3 VISION trial, PSMA-RLT combined with prior or concurrent ARB was reported to improve both rPFS and OS (NCT03511664) [8][9][10]. Several studies reported that AR suppresses PSMA transcription while ADT/ARB leads to derepression [11][12][13][14][15][16].…”

Impact of Androgen Receptor Activity on Prostate-Specific Membrane Antigen Expression in Prostate Cancer Cells

“…However, in line with reported PCa heterogeneity, PSMA is also heterogeneously expressed. Low PSMA protein levels have been reported as possible resistance mechanisms to PSMA-based radioligand diagnostic and therapies [39][40][41][42]. For this reason, the study of FOLH1 gene regulation came into scientific focus to improve the effectiveness of PSMA-targeted diagnostics and therapies.…”