Analysing the tumor transcriptome of prostate cancer to predict efficacy of Lu-PSMA therapy

Abstract

Rationale: ¹⁷⁷Lu-PSMA ([¹⁷⁷Lu]Lutetium-PSMA-617) therapy is an effective treatment option for patients with prostate specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer, but still shows a non-responder rate of approximately 30%. Combination regimes of programmed death-ligand 1 (PD-L1) inhibition and concomitant ¹⁷⁷Lu-PSMA therapy have been proposed to increase the response rate. However, the interplay of immune landscape and ¹⁷⁷Lu-PSMA therapy efficacy is poorly understood.

Methods: Between March 2018 and December 2021, a total of 168 patients were referred to ¹⁷⁷Lu-PSMA therapy in our department and received a mean total dose of 21.9 GBq (three cycles in mean). All patients received baseline PSMA positron emission tomography to assess the PSMA uptake. The histopathological specimen of the primary prostate tumor was available with sufficient RNA passing quality control steps for genomic analysis in n=23 patients. In this subset of patients, tumor RNA transcriptomic analyses assessed 74 immune-related features in total, out of which n=24 signatures were not co-correlated and investigated further for outcome prognostication.

Results: In the subset of patients who received ¹⁷⁷Lu-PSMA therapy, PD-L1 was not significantly associated with OS (HR per SD change (95% CI) 0.74 (0.42 to 1.30); SD: 0.18; p=0.29). In contrast, PD-L2 signature was positively associated with longer OS (HR per SD change 0.46 (95% CI 0.29 to 0.74); SD: 0.24; p=0.001; median OS 17.2 vs 5.7 months in higher vs lower PD-L2 patients). In addition, PD-L2 signature correlated with PSA-response (ϱ=-0.46; p=0.04). The PD-L2 signature association with OS was significantly moderated by L-Lactatdehydrogenase (LDH) levels (Cox model interaction p=0.01).

Conclusion: Higher PD-L2 signature might be associated with a better response to ¹⁷⁷Lu-PSMA therapy and warrants further studies investigating additional immunotherapy. In contrast, PD-L1 was not associated with outcome. The protective effect of PD-L2 signature might be present only in men with lower LDH levels.

Keywords: Prostatic Neoplasms; Radiotherapy; Tumor Biomarkers.