scholarly journals Targeting Poly(ADP-Ribose) Polymerase and the c-Myb-Regulated DNA Damage Response Pathway in Castration-Resistant Prostate Cancer

2014 ◽  
Vol 7 (326) ◽  
pp. ra47-ra47 ◽  
Author(s):  
L. Li ◽  
W. Chang ◽  
G. Yang ◽  
C. Ren ◽  
S. Park ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Damage Response ◽  
Dna Damage Response Pathway

A phase II study of M6620 in combination with carboplatin compared with docetaxel in combination with carboplatin in metastatic castration-resistant prostate cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS5597-TPS5597
Author(s):  
Atish Dipankar Choudhury ◽  
Wanling Xie ◽  
Mamta Parikh ◽  
Daniel Lee ◽  
Elizabeth R Kessler ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Synergistic Activity ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Recist 1.1 ◽  
Damage Response ◽  
Pre Treatment ◽  
Carboplatin Auc

TPS5597 Background: Alterations in DNA damage repair genes are common in metastatic castration-resistant prostate cancer (mCRPC), and are implicated in responses to carboplatin, PARP inhibitors and immunotherapeutics. The ATR kinase is involved in the DNA damage response, and ATR inhibitors have been demonstrated in preclinical models to have synergistic activity with platinum compounds due to induction of replication stress. Methods: This is a randomized open-label Phase 2 study of the ATR inhibitor M6620 + carboplatin vs. docetaxel + carboplatin in mCRPC. Patients (pts) previously treated with at least one secondary hormonal therapy and taxane-based chemotherapy undergo mandatory pre-treatment biopsy and are randomized 1:1 to receive Arm A (docetaxel 60 mg/m2 day 1 + carboplatin AUC 4 day 1) or Arm B (M6620 90 mg/m2 days 2,9 + carboplatin AUC 5 day 1) every 21 days. Pts randomized to Arm A who are not candidates for docetaxel receive carboplatin AUC 5 monotherapy. Stratification factors are 1) prior PARP inhibitor (yes vs. no) and 2) evaluable disease by RECIST 1.1 (yes vs. no). Pts on Arm A crossover to Arm B (M6620+carboplatin) at the earlier of PSA or radiographic progression. For the primary endpoint of overall response rate (ORR; PSA reduction by ≥ 50% or radiographic response by RECIST 1.1), with 65 pts on each arm (total N = 130), there will be 80% power to distinguish ORR of 40% vs. 20% using a chi-square test (one sided α = 0.05). 136 pts will be enrolled to account for 5% dropout. Secondary endpoints include time to PSA progression, radiographic PFS, PFS by PCWG3 criteria, safety and adverse events in each arm. Biomarker studies include whole exome sequencing, RAD51 focus formation, and ATM IHC from tumor specimens. Circulating cell-free DNA from pre-treatment and progression plasma specimens will undergo ultra-low pass whole genome sequencing and deep targeted sequencing. The goal of this study is to expand therapeutic options in mCRPC through a novel approach to targeting the DNA damage response, and to identify biomarkers associating with response and resistance to both standard and trial therapy. Enrollment began June 2019 (NCI/ETCTN #10191, NCT03517969). Clinical trial information: NCT03517969 .

A phase II study of M6620 in combination with carboplatin compared with docetaxel in combination with carboplatin in metastatic castration-resistant prostate cancer.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS252-TPS252
Author(s):  
Atish Dipankar Choudhury ◽  
Wanling Xie ◽  
Mamta Parikh ◽  
Daniel Lee ◽  
Elizabeth R. Kessler ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Synergistic Activity ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Recist 1.1 ◽  
Damage Response ◽  
Pre Treatment ◽  
Carboplatin Auc

TPS252 Background: Alterations in DNA damage repair genes are common in metastatic castration-resistant prostate cancer (mCRPC), and are implicated in responses to carboplatin, PARP inhibitors and immunotherapeutics. The ATR kinase is involved in the DNA damage response, and ATR inhibitors have been demonstrated in preclinical models to have synergistic activity with platinum compounds due to induction of replication stress. Methods: This is a randomized open-label Phase 2 study of the ATR inhibitor M6620 + carboplatin vs. docetaxel + carboplatin in mCRPC. Patients (pts) previously treated with at least one secondary hormonal therapy and taxane-based chemotherapy undergo mandatory pre-treatment biopsy and are randomized 1:1 to receive Arm A (docetaxel 60 mg/m2 day 1 + carboplatin AUC 4 day 1) or Arm B (M6620 90 mg/m2 days 2,9 + carboplatin AUC 5 day 1) every 21 days. Pts randomized to Arm A who are not candidates for docetaxel receive carboplatin AUC 5 monotherapy. Stratification factors are 1) prior PARP inhibitor (yes vs. no) and 2) evaluable disease by RECIST 1.1 (yes vs. no). Pts on Arm A crossover to Arm B (M6620+carboplatin) at the earlier of PSA or radiographic progression. For the primary endpoint of overall response rate (ORR; PSA reduction by ≥ 50% or radiographic response by RECIST 1.1), with 65 pts on each arm (total N = 130), there will be 80% power to distinguish ORR of 40% vs. 20% using a chi-square test (one sided α = 0.05). 136 pts will be enrolled to account for 5% dropout. Secondary endpoints include time to PSA progression, radiographic PFS, PFS by PCWG3 criteria, safety and adverse events in each arm. Biomarker studies include whole exome sequencing, RAD51 focus formation, and ATM IHC from tumor specimens. Circulating cell-free DNA from pre-treatment and progression plasma specimens will undergo ultra-low pass whole genome sequencing and deep targeted sequencing. The goal of this study is to expand therapeutic options in mCRPC through a novel approach to targeting the DNA damage response, and to identify biomarkers associating with response and resistance to both standard and trial therapy. Enrollment began June 2019 (NCI/ETCTN #10191). Clinical trial information: NCT03517969.

scholarly journals Effect of DNA damage response mutations on prostate cancer prognosis: a systematic review

2019 ◽  
Vol 15 (28) ◽  
pp. 3283-3303 ◽  
Author(s):  
Stephanie L Swift ◽  
Shona H Lang ◽  
Heath White ◽  
Kate Misso ◽  
Jos Kleijnen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Systematic Review ◽  
Dna Damage ◽  
Clinical Outcomes ◽  
Dna Damage Response ◽  
Parp Inhibitor ◽  
Cancer Prognosis ◽  
Castration Resistant ◽  
Damage Response ◽  
Brca1 Brca2

The prognosis of men with prostate cancer (PC) with mutations in DNA damage response ( DDR) genes undergoing different treatments is unclear. This systematic review compared clinical outcomes in PC patients with DDR mutations ( DDR+) versus no mutations ( DDR-). 14 resources plus gray literature were searched for studies in PC and subgroups (castration-resistant PC, metastatic PC and metastatic castration-resistant PC) by DDR gene ( ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C) mutation status. From 11,648 records, 26 studies were included. For mCRPC, six studies reported comparative efficacy for key outcomes. Improvements in several clinical outcomes were observed for DDR+ (vs DDR-) after PARP inhibitor therapy or immunotherapy. DDR+ PC patients may have improved outcomes depending on the treatment they undergo.

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