scholarly journals Evaluation of the Efficacy of PARP Inhibitors in Metastatic Castration-Resistant Prostate Cancer: A Systematic Review and Meta-Analysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Kan Wu ◽  
Jiayu Liang ◽  
Yanxiang Shao ◽  
Sanchao Xiong ◽  
Shuyang Feng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trials ◽  
Meta Analysis ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Parp Inhibitors ◽  
Cochrane Central Register ◽  
Castration Resistant Prostate Cancer ◽  
Effective Treatment Option ◽  
Castration Resistant

Background: Poly(ADP-ribose) polymerase (PARP) inhibitors have breakthrough designations for metastatic castration-resistant prostate cancer (mCRPC). We performed a meta-analysis of current clinical trials to evaluate the efficacy of PARP inhibitors in mCRPC patients based on their genetic status.Methods: On August 2020, PubMed, Scopus, Embase, Cochrane Central Register of Controlled Trials, and Web of Science were searched for phase II/III clinical studies on PARP inhibitors in mCRPC patients. Data were extracted independently by two investigators and analyzed using Review Manager software version 5.3. Primary endpoints included overall response rate (ORR) and progression-free survival (PFS).Results: Nine clinical trials were identified and analyzed for the clinical benefit of PARP inhibitors in mCRPC patients (n = 1,219). Pooled analyses demonstrated that PARP inhibitors could provide a significant improvement of ORR and PFS in patients with homologous recombination deficiency (HRD) when compared with non-HRD patients. Within the HRD subgroup, BRCA mutation patients achieved significantly higher ORR [odds ratio (OR): 9.97, 95% confidence interval (CI): 6.08–16.35] and PFS rates at 12 months (OR: 3.23, 95% CI: 1.71–6.10) when compared with BRCA wild-type patients. Furthermore, patients harboring HRD without BRCA mutations have a higher objective response after PARP inhibitor treatment compared with non-HRD patients.Conclusion: PARP inhibitor is an effective treatment option for mCRPC patients with mutations in genes related to the HR DNA repair pathway when compared with non-HRD patients. In addition to BRCA mutations, other HRD-related gene aberrations may also be used as novel biomarkers to predict the efficacy of PARP inhibitors.

scholarly journals Differential Activity of PARP Inhibitors in BRCA1- Versus BRCA2-Altered Metastatic Castration-Resistant Prostate Cancer

2021 ◽  
pp. 1200-1220
Author(s):  
Fadi Taza ◽  
Albert E. Holler ◽  
Wei Fu ◽  
Hao Wang ◽  
Nabil Adra ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Parp Inhibitor ◽  
Specific Antigen ◽  
Germline Mutations ◽  
Parp Inhibitors ◽  
Parp Inhibition ◽  
Missense Mutations ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

PURPOSE Two poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and rucaparib) are US Food and Drug Administration–approved for patients with metastatic castration-resistant prostate cancer (mCRPC) harboring BRCA1/ 2 mutations, but the relative efficacy of PARP inhibition in BRCA1- versus BRCA2-altered mCRPC is understudied. METHODS We conducted a multicenter retrospective analysis involving 12 sites. We collected genomic and clinical data from 123 patients with BRCA1/ 2-altered mCRPC who were treated with PARP inhibitors. The primary efficacy end point was the prostate-specific antigen (PSA) response (≥ 50% PSA decline) rate. Secondary end points were PSA progression-free survival (PSA-PFS), clinical or radiographic PFS, and overall survival. We compared clinical outcomes, and other genomic characteristics, among BRCA1- versus BRCA2-altered mCRPC. RESULTS A total of 123 patients (13 BRCA1 and 110 BRCA2) were included. PARP inhibitors used were olaparib (n = 116), rucaparib (n = 3), talazoparib (n = 2), and veliparib (n = 2). At diagnosis, 72% of patients had Gleason 8-10 disease. BRCA1 patients were more likely to have metastatic disease at presentation (69% v 37%; P = .04). Age, baseline PSA, metastatic distribution, and types of previous systemic therapies were similar between groups. There were equal proportions of germline mutations (51% v 46%; P = .78) in both groups. BRCA1 patients had more monoallelic (56% v 41%; P = .49) and concurrent TP53 (55% v 36%; P = .32) mutations. PSA50 responses in BRCA1- versus BRCA2-altered patients were 23% versus 63%, respectively ( P = .01). BRCA2 patients achieved longer PSA-PFS (HR, 1.94; 95% CI, 0.92 to 4.09; P = .08), PFS (HR, 2.08; 95% CI, 0.99 to 4.40; P = .05), and overall survival (HR, 3.01; 95% CI, 1.32 to 6.83; P = .008). Biallelic (compared with monoallelic) mutations, truncating (compared with missense) mutations, and absence of a concurrent TP53 mutation were associated with PARP inhibitor sensitivity. CONCLUSION PARP inhibitor efficacy is diminished in BRCA1- versus BRCA2-altered mCRPC. This is not due to an imbalance in germline mutations but might be related to more monoallelic mutations and/or concurrent TP53 alterations in the BRCA1 group.

Genetic biomarkers to guide poly(ADP‐ribose) polymerase inhibitor precision treatment of prostate cancer

2020 ◽  
Vol 21 (15) ◽  
pp. 1101-1115
Author(s):  
Reka Varnai ◽  
Csilla Sipeky
Keyword(s):  
Prostate Cancer ◽  
Clinical Trials ◽  
Parp Inhibitors ◽  
Castration Resistant Prostate Cancer ◽  
Repair Gene ◽  
Castration Resistant ◽  
Damage Repair ◽  
Precision Therapy ◽  
Polymerase Inhibitor ◽  
Near Future

Precision therapy for a subgroup of genetically defined metastatic castration-resistant prostate cancer patients may become a reality in the near future. DNA damage repair gene mutated prostate cancer might be vulnerable to treatment with PARP inhibitors (PARPi). PARPi clinical trials for prostate cancer investigate both germline and somatic genomic alterations of 43 genes for the applicability as genomic biomarker of PARPi sensitivity. Clinical trials with preliminary results show that BRCA2 and BRCA1, but also ATM, additionally BRIP1, FANCA, CDK12 and PALB2 may affect clinical end points, and may be potential candidates for genome-guided patient selection in PARPi treatment of prostate cancer.

scholarly journals Real-world genetic testing patterns in metastatic castration-resistant prostate cancer

2021 ◽  
Author(s):  
Neal Shore ◽  
Raluca Ionescu-Ittu ◽  
Lingfeng Yang ◽  
François Laliberté ◽  
Malena Mahendran ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Genetic Testing ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Recombination Repair ◽  
Testing Patterns ◽  
Oncology Center ◽  
Gene Alterations

Aim: To assess the patterns of genetic testing for homologous recombination repair mutations in patients with metastatic castration-resistant prostate cancer (mCRPC) pre-PARP inhibitors approval. Patients & methods: mCRPC patients were selected in an oncology electronic medical records database. Patterns and predictors of testing for ATM, BRCA1/2, CDK12, PALB2 and FANCA gene alterations were assessed. Results: Of 5213 mCRPC patients, 674 (13%) had a documented genetic test. The number of tested patients increased from 1 in 2013 to 313 in 2018 (out of 3161 and 3010 clinically active patients, respectively). Receiving care in an academic oncology center (versus a community-based center) strongly predicted genetic testing (hazard ratio = 2.41). Conclusion: The use of and access to genetic testing pre-PARP inhibitor approval was suboptimal.

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