Patients Resistant Against PSMA-Targeting α-Radiation Therapy Often Harbor Mutations in DNA Damage-Repair–Associated Genes

Abstract

Prostate-specific membrane antigen (PSMA) targeting alpha-radiation therapy (TAT) is an emerging treatment modality for metastatic castration-resistant prostate cancer. There is a subgroup of patients with poor response despite sufficient expression of PSMA in their tumors. The aim of this work was to characterize PSMA-TAT nonresponding lesions by targeted next-generation sequencing (tNGS). Methods: Out of 60 patients treated with 225 Ac-PSMA-617, we identified 10 patients that presented with a poor response despite sufficient tumor-uptake in PSMA-PET/CT. We were able to perform CT-guided biopsies with histologic validation of the non-responding lesions in seven of these non-responding patients. Specimens were analyzed by tNGS interrogating 37 DNA damage-repair associated genes. Results: In the seven tumor samples analyzed, we found a total of 15 whole-gene deletions, deleterious or presumably deleterious mutations affecting TP53 (n=3); CHEK2 (n=2), ATM (n=2); BRCA1, BRCA2, PALB2, MSH2, MSH6, NBN, FANCB and PMS1 (n=1 each). The average number of deleterious or presumably deleterious mutations was 2.2 (range, 0-6) per patient. In addition, several variants of unknown significance in ATM, BRCA1, MSH2, SLX4, ERCC-and various FANC-genes were detected. Conclusion: Patients with resistance to PSMA-TAT despite PSMA-positivity frequently harbor mutations in DNA-damage-repair and checkpoint genes. While the causal role of these alterations in the patient outcome remains to be determined, our findings encourage future studies combining PSMA-TAT and DNA-damage-repair targeting agents such as Poly(ADPribose)-Polymerase inhibitors.

Atomic Nanogenerators in Targeted Alpha Therapies: Curie’s Legacy in Modern Cancer Management

“…However, with the growing numbers of patients treated with TAT, the occurrence of non-responders or individuals who will relapse shortly after the treatment can be observed ( Figure 6). Targeted next-generation sequencing (tNGS) in responding vs. non-or only poor responding patients despite PSMA positivity to [ 225 Ac]Ac-PSMA-617 therapy revealed that DNA damage-repair and checkpoint genes are frequently mutated in poor and non-responders [111]. The mechanisms as to how the inherent or acquired resistances and gene mutations develop are far from being understood, and no strategies for risk stratification of patients exist yet.…”

Advances in Precision Oncology: Targeted Thorium-227 Conjugates As a New Modality in Targeted Alpha Therapy

“…Resistance to therapy, which develops to some cancer drugs, is unlikely to occur to α-particle-emitting radionuclides, 26 although a high prevalence of mutations in the DNA damage response (DDR) genes was reported in a small group of patients who had not responded to 225 Ac-prostate-specific membrane antigen (PSMA)-617 treatment. 27 Moreover, the high energy of α particles, delivered within a small area in the tumor, damage cancer cells independently of local oxygen levels, thus overcoming hypoxia-induced resistance to therapy. 26 , 28 Notably, due to their short path length, potent radiation, and normal tissue sparing, TTCs may be a particularly attractive therapeutic choice for controlling the growth of micrometastatic cancer deposits in patients with disseminated cancer.…”

Preclinical and Clinical Status of PSMA-Targeted Alpha Therapy for Metastatic Castration-Resistant Prostate Cancer

“…Around 20% of patients treated with 225 Ac-PSMA-617 have a poor response (Table 5) or early resistance against 225 Ac-PSMA-617 [107], despite sufficient expression of PSMA and uptake of 225 Ac-PSMA-617 in their tumors [192]. Several combination treatments with PSMA-TAT have been proposed [173,192,193]. Their goal is to increase PSMA-TAT efficacy by using therapies with different action mechanisms together with TAT, keeping toxic effects to a minimum.…”

“…A single course of tandem therapy with low-activity 225 Ac-PSMA-617 and full-activity 177 Lu-PSMA-617 has enhanced response to PSMA-RLT and minimized xerostomia severity in men with late-stage/end-stage mCRPC [173,194]. There is a subgroup of patients (∼17%) with poor response to 225 Ac-PSMA-617 who harbor mutations in DNA damage-repair and checkpoint genes [192]. Combining PSMA-TAT and DNA damage-repair-targeting agents, such as poly(ADP-ribose)-polymerase inhibitors, have been suggested for these patients [192].…”

“…There is a subgroup of patients (∼17%) with poor response to 225 Ac-PSMA-617 who harbor mutations in DNA damage-repair and checkpoint genes [192]. Combining PSMA-TAT and DNA damage-repair-targeting agents, such as poly(ADP-ribose)-polymerase inhibitors, have been suggested for these patients [192]. Lastly, it has been hypothesized that PSMA-TAT may increase tumor immunogenicity, and the use of immune checkpoint inhibitors may improve efficacy [102].…”