AR and PI3K Genomic Profiling of Cell-free DNA Can Identify Poor Responders to Lutetium-177-PSMA Among Patients with Metastatic Castration-resistant Prostate Cancer

Jan Vanwelkenhuyzen; Eva Van Bos; Siska Van Bruwaene; Karl Lesage; Alex Maes; Sezgin Üstmert; Filip Lavent; Laurence Beels; Henrik Grönberg; Piet Ost; Johan Lindberg; Bram De Laere

doi:10.1016/j.euros.2023.05.008

AR and PI3K Genomic Profiling of Cell-free DNA Can Identify Poor Responders to Lutetium-177-PSMA Among Patients with Metastatic Castration-resistant Prostate Cancer

Eur Urol Open Sci. 2023 May 30:53:63-66. doi: 10.1016/j.euros.2023.05.008. eCollection 2023 Jul.

Authors

Jan Vanwelkenhuyzen^{1

2

3}, Eva Van Bos⁴, Siska Van Bruwaene⁴, Karl Lesage⁴, Alex Maes⁵, Sezgin Üstmert⁵, Filip Lavent⁵, Laurence Beels⁵, Henrik Grönberg⁶, Piet Ost^{1

2

7}, Johan Lindberg⁶, Bram De Laere^{1

2

6}

Affiliations

¹ Department of Human Structure and Repair, Ghent University, Ghent, Belgium.
² Cancer Research Institute Ghent, Ghent, Belgium.
³ Centre for Medical Biotechnology (CMB) VIB, Zwijnaarde, Belgium.
⁴ Department of Urology, AZ Groeninge, Kortrijk, Belgium.
⁵ Department of Nuclear Medicine, AZ Groeninge, Kortrijk, Belgium.
⁶ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁷ Department of Radiotherapy, GZA Sint-Augustinus, Antwerp, Belgium.

Abstract

Lutetium-177 prostate-specific membrane antigen radioligands (¹⁷⁷Lu-PSMA) are new therapeutic agents for the treatment of metastatic castration-resistant prostate cancer (mCRPC). We evaluated the prognostic value of circulating tumour DNA (ctDNA) profiling in patients with mCRPC starting treatment with ¹⁷⁷Lu-PSMA I&T. Between January 2020 and October 2022, patients with late-stage mCRPC (n = 57) were enrolled in a single-centre observational cohort study. Genomic alterations in the AR gene, PI3K signalling pathway, TP53, and TMPRSS2-ERG were associated with progression-free survival (PFS) on Kaplan-Meier and multivariable Cox regression analyses. Median PFS of 3.84 mo (95% confidence interval [CI] 3.3-5.4) was observed, and 21/56 (37.5%) evaluable patients experienced a prostate-specific antigen response of ≥50% during treatment. Among 46 patients who provided a blood sample for profiling before ¹⁷⁷Lu-PSMA treatment. ctDNA was detected in 39 (84.8%); higher ctDNA was correlated with shorter PFS. Genomic structural rearrangements in the AR gene (hazard ratio [HR] 9.74, 95% confidence interval [CI] 2.4-39.5; p = 0.001) and alterations in the PI3K signalling pathway (HR 3.58, 95% CI 1.41-9.08; p = 0.007) were independently associated with poor ¹⁷⁷Lu-PSMA prognosis on multivariable Cox regression. Prospective evaluation of these associations in biomarker-driven trials is warranted.

Patient summary: We examined cell-free DNA in blood samples from patients with advanced metastatic prostate cancer who started treatment with lutetium-177-PSMA, a new radioligand therapy. We found that patients with genetic alterations in the androgen receptor gene or PI3K pathway genes did not experience a lasting benefit from lutetium-177-PSMA.

Keywords: Biomarker; Cell-free DNA; Circulating tumour DNA; Liquid biopsy; Lutetium-177-PSMA; Metastatic castration-resistant prostate cancer.