Oncological Response and Predictive Biomarkers for the Checkpoint Inhibitors in Castration-Resistant Metastatic Prostate Cancer: A Systematic Review and Meta-Analysis

Abstract

Recently, checkpoint inhibitors have been investigated in metastatic prostate cancer, however their overall effect is unclear and needs to be further investigated. Objectives: The aim of this systematic review is to investigate the oncological response of metastatic castration-resistant prostate cancer patients to immune checkpoint inhibitors. Methods: Based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement, a systematic review of the literature was conducted through online electronic databases and the American Society of Clinical Oncology (ASCO) Meeting Library. Eligible publications were selected after a staged screening and selection process. RevMan 5.4 software was employed to run the quantitative analysis and forest plots. Risk of bias assessment was conducted using the Cochrane tool and Newcastle–Ottawa Scale for the randomized and non-randomized trials, respectively. Results: From the 831 results retrieved, 8 studies including 2768 patients were included. There was no significant effect on overall survival (OS) (overall response (OR) = 0.98; Z = 0.42; p = 0.67). Meanwhile, progression-free survival (PFS) was significantly better with immune checkpoint inhibitors administration (OR = 0.85; Z = 3.9; p < 0.0001). The subgroup analysis for oncological outcomes based on programmed death ligand 1 (PD-L1) positivity status displayed no significant effect, except on prostate-specific antigen response rate (PSA RR) (OR = 3.25; Z = 2.29; p = 0.02). Based on DNA damage repair (DDR), positive patients had a significantly better PFS and a trend towards better OS and overall response rate (ORR); the ORR was 40% in positive patients compared to 20% in the negative patients (OR = 2.46; Z = 1.3; p = 0.19), while PSA RR was 23.5% compared to 14.3% (OR = 1.88; Z = 0.88; p = 0.38). Better PFS was clearly associated with DDR positivity (OR = 0.70; Z = 2.48; p = 0.01) with a trend towards better OS in DDR positive patients (OR = 0.71; Z = 1.38; p = 0.17). Based on tumor mutation burden (TMB), ORR was 46.7% with high TMB versus 8.8% in patients with low TMB (OR = 11.88; Z = 3.0; p = 0.003). Conclusions: Checkpoint inhibitors provide modest oncological advantages in metastatic castration-resistant prostate cancer. There are currently no good predictive indicators that indicate a greater response in some patients.

Serum multi-cytokines screening identifies TRAIL and IL-10 as probable new biomarkers for prostate health index diagnostic utility adjustment in grey zone aggressive prostate cancer detection: A single-center data in China

“…Consistent with the results of recent studies the risk factor immune response was found to be related to aggressive prostate cancer progression and resistance to drug treatment ( 24 – 26 ), which may further direct urologists for grey zone aggressive prostate cancer early risk stratification. Functioning as one of the tumor necrosis factor ligand family, TRAIL has been reported to induce apoptosis in tumor cells preferentially.…”

Characterization of 7-Methylguanosine Identified Biochemical Recurrence and Tumor Immune Microenvironment in Prostate Cancer

“…The m7Gscore was significantly positively related to TMB and several immune checkpoints expression (PDCD1, CD274, PDCD1LG2, TIGIT, IDO1, and CTLA4). Immunotherapy is more likely to respond effectively to PCa patients with a high level of TMB or immune checkpoints ( 48 , 49 ). Then we assessed the sensitivity to chemotherapy and endocrine drugs in the m7Gscore-defined groups.…”

The role of DNA damage repair (DDR) system in response to immune checkpoint inhibitor (ICI) therapy

“…Indeed, even when compared to existing predictive markers such as TMB and PD-L1 expression, DDR mutation demonstrates an excellent prognostic effect [ 20 , 22 , 47 , 48 ]. In addition, DDR status predicts different clinical outcomes between immunotherapy and non-immunotherapy [ 20 , 72 ].…”

“…Among the patients treated with ICB, those with homologous recombination deficiency (HRD) or DDR mutation exhibited better response [13,47]. For patients with gastrointestinal cancer, advanced urothelial cancer, and metastatic prostate cancer treated with anti-PD-(L)1, DDR changes can lead to the prolongation of overall survival (OS) and progression-free survival (PFS) [47,48]. Furthermore, as the number of DDR changes increases, the objective response rate (ORR) and the durable clinical benefit (DCB) increased significantly [47,49].…”

“…In addition, the characteristics used to divide patients with hepatocellular carcinoma (HCC) into the DDR activation or inhibition subgroup can effectively help distinguish the clinical and molecular features of HCC, and predict different immunotherapy responses and prognoses [71,72]. Indeed, even when compared to existing predictive markers such as TMB and PD-L1 expression, DDR mutation demonstrates an excellent prognostic effect [20,22,47,48]. In addition, DDR status predicts different clinical outcomes between immunotherapy and non-immunotherapy [20,72].…”