Dataset Information

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.

SUBMITTER: Figg WD

PROVIDER: S-EPMC3758779 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Publications

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

Figg William D WD Chau Cindy H CH Madan Ravi A RA Gulley James L JL Gao Rui R Sissung Tristan M TM Spencer Shawn S Beatson Melony M Aragon-Ching Jeanny J Steinberg Seth M SM Dahut William L WL

Clinical genitourinary cancer 20130517 3

<h4>Background</h4>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.<h4>Patients and methods</h4>Twenty-four patients were enrolled in this single arm study. The primary objective was to determine if the presence of ERCC1 Asn118Asn (N118N, ...[more]

PMID: 23684781

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Project description:BACKGROUND:Bone metastases in patients with metastatic castration-resistant prostate cancer (mCRPC) are associated with debilitating pain and functional compromise. OBJECTIVE:To compare pain palliation as the primary endpoint for cabozantinib versus mitoxantrone-prednisone in men with mCRPC and symptomatic bone metastases using patient-reported outcome measures. DESIGN, SETTING, AND PARTICIPANTS:A randomized, double-blind phase 3 trial (COMET-2; NCT01522443) in men with mCRPC and narcotic-dependent pain from bone metastases who had progressed after treatment with docetaxel and either abiraterone or enzalutamide. INTERVENTION:Cabozantinib 60mg once daily orally versus mitoxantrone 12mg/m2 every 3wk plus prednisone 5mg twice daily orally. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:The primary endpoint was pain response at week 6 confirmed at week 12 (?30% decrease from baseline in patient-reported average daily worst pain score via the Brief Pain Inventory without increased narcotic use). The planned sample size was 246 to achieve ?90% power. RESULTS AND LIMITATIONS:Enrollment was terminated early because cabozantinib did not demonstrate a survival benefit in the companion COMET-1 trial. At study closure, 119 participants were randomized (cabozantinib: N=61; mitoxantrone-prednisone: N=58). Complete pain and narcotic use data were available at baseline, week 6, and week 12 for 73/106 (69%) patients. There was no significant difference in the pain response with cabozantinib versus mitoxantrone-prednisone: the proportions of responders were 15% versus 17%, a -2% difference (95% confidence interval: -16% to 11%, p=0.8). Barriers to accrual included pretreatment requirements for a washout period of prior anticancer therapy and a narcotic optimization period to maximize analgesic dosing. CONCLUSIONS:Cabozantinib treatment did not demonstrate better pain palliation than mitoxantrone-prednisone in heavily pretreated patients with mCRPC and symptomatic bone metastases. Future pain-palliation trials should incorporate briefer timelines from enrollment to treatment initiation. PATIENT SUMMARY:Cabozantinib was not better than mitoxantrone-prednisone for pain relief in patients with castration-resistant prostate cancer and debilitating pain from bone metastases.

Dataset Information

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

Background

Patients and methods

Results

Conclusions

Publications

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

Similar Datasets

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