The prevalence and prognosis of next-generation therapeutic targets in metastatic castration-resistant prostate cancer.

The success of the PROfound, IPATential150, and TheraP trials promoted the transition from sequential treatment to therapeutic targets (TTs)-guided precision treatment in metastatic castration-resistant prostate cancer (mCRPC). The objective of this study was to evaluate the prevalence and prognostic value of TTs from these three trials. All included Chinese mCRPC patients underwent circulating tumor DNA (ctDNA) sequencing, PTEN status assessment, and dual-tracer [ Ga-prostate-specific membrane antigen (PSMA) and F-fluorodexyglucose (FDG)] positron emission tomography/computed tomography (PET/CT). Previous treatment with cabazitaxel, Lu-PSMA or olaparib was unallowed. Patients with known significant sarcomatoid or spindle cell or neuroendocrine small cell components were also excluded. TTs were defined as positive as follows: (a) high PSMA and no PSMA-/FDG+ disease on dual-tracer PET/CT scans; (b) defects in homologous recombination repair (HRR) genes in ctDNA; and (c) loss of PTEN immunohistochemistry staining in tumor tissue. The prevalence and prognostic value on progression-free survival (PFS) of TTs were evaluated. A total of 106 consecutive mCRPC patients were included. The prevalence of positive PET/CT, HRR defect, and PTEN loss was 30%, 29% and 16%, respectively. Sixty-three patients had at least one TT. Metastatic volume (odds ratio = 5.0; P = 0.017) was the only independent factor of positive TT in multivariate analysis. Seventy-four patients received abiraterone after TT screening. Patients with positive PET/CT (P = 0.011) and HRR defect (P = 0.002) had a significantly shorter PFS after receiving abiraterone than patients with negative TTs. However, PTEN status was unrelated to PFS, which may be due to a less number of patients with PTEN loss (P = 0.952). Overall, patients with any positive TTs had a significantly shorter PFS after abiraterone than patients with negative TTs (P = 0.009). Nearly 60% of Chinese patients with mCRPC who had a poor prognosis on abiraterone were candidates for precision treatments based on the specific criteria of TTs.