Phase II study of satraplatin and prednisone in patients with metastatic castration-resistant prostate cancer: a pharmacogenetic assessment of outcome and toxicity.

Abstract

BACKGROUND:

We assessed the effect of excision repair cross-complementing group 1 (ERCC1) and x-ray cross-complementing group 1 (XRCC1) gene polymorphisms on treatment outcomes with satraplatin and prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel-based therapy.

PATIENTS AND METHODS:

Twenty-four patients were enrolled in this single arm study. The primary objective was to determine if the presence of ERCC1 Asn118Asn (N118N, 500C>T, rs11615) and XRCC1 Arg399Gln (R399Q, 1301G>A, rs25487) genetic variants might be associated with an impact on progression-free survival (PFS); secondary objectives included overall response, survival, and toxicity.

RESULTS:

After population stratification by race, white patients carrying heterozygous or variant genotypes at the ERCC1 C>T locus had a >3-fold longer median PFS (5.8 vs. 1.8 months; 2P = .18, adjusted) and 5-fold longer median overall survival (OS) (15.7 vs. 3.2 months; 2P = .010, adjusted) than did patients carrying only wild-type alleles. For the XRCC1 G>A variant, without regard to race, patients carrying the wild-type GG alleles had a longer PFS (9.3 months) than those carrying GA or AA alleles (2.7 months; 2P = .02). Similarly, those carrying GG alleles did not reach median OS, whereas those carrying GA or AA alleles had a median OS of 9.6 months (2P = .12, adjusted). Multivariable analysis by using Cox proportional hazards modeling demonstrated that only XRCC1 was associated with PFS.

CONCLUSIONS:

To our knowledge, this is the first prospective study to date in patients with metastatic castration-resistant prostate cancer that describes predictive germline polymorphisms of ERCC1 and XRCC1 for assessing the clinical activity of satraplatin.

• Authors: William D Figg, Cindy H Chau, Ravi A Madan, James L Gulley, Rui Gao, Tristan M Sissung, Shawn Spencer, Melony Beatson, Jeanny Aragon-Ching, Seth M Steinberg, William L Dahut
• Journal: Clinical genitourinary cancer (Clin Genitourin Cancer) Vol. 11 Issue 3 Pg. 229-37 (Sep 2013) ISSN: 1938-0682 [Electronic] United States
• PMID: 23684781 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Intramural)
• Copyright: Published by Elsevier Inc.

Chemical References

• DNA-Binding Proteins
• Organoplatinum Compounds
• Taxoids
• X-ray Repair Cross Complementing Protein 1
• XRCC1 protein, human
• Docetaxel
• satraplatin
• ERCC1 protein, human
• Endonucleases
• Prednisone

Topics

• Adenocarcinoma (drug therapy, genetics)
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, pharmacology, therapeutic use)
• DNA-Binding Proteins (genetics)
• Disease-Free Survival
• Docetaxel
• Drug Resistance, Neoplasm (genetics)
• Endonucleases (genetics)
• Genotype
• Humans
• Male
• Middle Aged
• Neoplasm Metastasis (drug therapy)
• Organoplatinum Compounds (adverse effects, pharmacology, therapeutic use)
• Polymorphism, Single Nucleotide
• Prednisone (adverse effects, pharmacology, therapeutic use)
• Prostatic Neoplasms, Castration-Resistant (drug therapy, genetics)
• Taxoids (therapeutic use)
• Treatment Outcome
• X-ray Repair Cross Complementing Protein 1