PROREPAIR-B: A prospective cohort study of DNA repair defects in metastatic castration resistant prostate cancer (mCRPC)

Marcos, E. Castro; Laorden, N. Romero; Rodriguez, J.M. Piulats; Pozo, Ángela del; Sáez, M.I.; Medina-Colmenero, A.; Puente, Javier; Silla-Castro, Juan Carlos; Mejorada, R. Lozano; García-Carbonero, I.; Rivera, L.; Vidal, María José Méndez; Barrera, Rafael; Parra, E.M. Fernandez; Flórez, Y. Cendón; Borrega, Pablo; Baamonde, M.A. Gonzalez Del Alba; Pritchard, Colin C.; Lapunzina, Pablo; Hidalgo, Daniel

doi:10.1093/annonc/mdx440.025

Cited by 4 publications

(2 citation statements)

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“…The efficacy of novel antiandrogens in HRR-deficient tumors is a matter of controversy. Whereas some authors suggest that enzalutamide or abiraterone treatment is associated with a poorer outcome 61,81,86, others either do not find a difference 87 or show a better outcome88,89. These studies are limited by the relatively low frequency of the mutations.…”

Section: Molecular Alterations In Cfdna From Advanced Prostate Cancermentioning

confidence: 99%

Circulating tumor DNA in advanced prostate cancer: transitioning from discovery to a clinically implemented test

González-Billalabeitia

Conteduca

Wetterskog

et al. 2018

Prostate Cancer Prostatic Dis

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Summary The genomic landscape of metastatic castration-resistant prostate cancer (mCRPC) differs from that of the primary tumor and is dynamic during tumor progression. The real-time and repeated characterization of this process via conventional solid tumor biopsies is challenging. Alternatively, circulating cell-free DNA (cfDNA) containing circulating tumor DNA (ctDNA) can be obtained from patient plasma using minimally disruptive blood draws and is amenable to sequential analysis. ctDNA has high overlap with the genomic sequences of biopsies from metastases and has the advantage of being representative of multiple metastases. The availability of techniques with high sensitivity and specificity, such as next-generation sequencing (NGS) and digital PCR, has greatly contributed to the development of the cfDNA field and enabled the detection of genomic alterations at low ctDNA fractions. In mCRPC, a number of clinically relevant genomic alterations have been tracked in ctDNA, including androgen receptor ( AR) aberrations, which have been shown to be associated with an adverse outcome to novel antiandrogen therapies, and alterations in homologous recombination repair (HRR) genes, which have been associated with a response to PARP inhibitors. Several clinical applications have been proposed for cfDNA analysis, including its use as a prognostic tool, as a predictive biomarker, to monitor tumor response and to identify novel mechanisms of resistance. To date, the cfDNA analysis has provided interesting results, but there is an urgent need for these findings to be confirmed in prospective clinical trials.

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Section: Molecular Alterations In Cfdna From Advanced Prostate Cancermentioning

confidence: 99%

Circulating tumor DNA in advanced prostate cancer: transitioning from discovery to a clinically implemented test

González-Billalabeitia

Conteduca

Wetterskog

et al. 2018

Prostate Cancer Prostatic Dis

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“…Men with localized prostate cancer harboring a germline BRCA2 variant have a shorter time to development of metastases, but several retrospective studies have recently suggested no worse outcome with AR targeting therapies or taxanes in mCRPC with aberrations in DNA-damage repair genes (4,5). The PRO-REPAIR B prospective observational study has identified worse PSA progression-free survival and cause-specific survival for patients harboring BRCA2 germline variants but no significant differences for other endpoints nor for other germline variants (6). These seemingly discordant reports highlight the challenges that underlie potential differences in outcome for (i) distinct aberrations within the same gene or different genes within the same class, (ii) germline carriers that do not suffer a second hit, (iii) technologies that have differential sensitivities and (iv) analysis in a worse prognosis group selected by virtue of being amenable to tumor biopsy or ctDNA fraction.…”

mentioning

confidence: 99%

Plasma DNA and Metastatic Castration-Resistant Prostate Cancer: The Odyssey to a Clinical Biomarker Test

Jayaram¹,

Wetterskog²,

Attard³

2018

Cancer Discov

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Demonstrating Bioequivalence for Two Dose Strengths of Niraparib and Abiraterone Acetate Dual-Action Tablets Versus Single Agents: Utility of Clinical Study Data Supplemented with Modeling and Simulation

Yu,

Hazra,

Jiao

et al. 2024

Clin Pharmacokinet

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Background and Objective The combination of niraparib and abiraterone acetate (AA) plus prednisone is under investigation for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) and metastatic castration-sensitive prostate cancer (mCSPC). Regular-strength (RS) and lower-strength (LS) dual-action tablets (DATs), comprising niraparib 100 mg/AA 500 mg and niraparib 50 mg/AA 500 mg, respectively, were developed to reduce pill burden and improve patient experience. A bioequivalence (BE)/bioavailability (BA) study was conducted under modified fasting conditions in patients with mCRPC to support approval of the DATs. Methods This open-label randomized BA/BE study (NCT04577833) was conducted at 14 sites in the USA and Europe. The study had a sequential design, including a 21-day screening phase, a pharmacokinetic (PK) assessment phase comprising three periods [namely (1) single-dose with up to 1-week run-in, (2) daily dose on days 1–11, and (3) daily dose on days 12–22], an extension where both niraparib and AA as single-agent combination (SAC; reference) or AA alone was continued from day 23 until discontinuation, and a 30-day follow-up phase. Patients were randomly assigned in a parallel-group design (four-sequence randomization) to receive a single oral dose of niraparib 100 mg/AA 1000 mg as a LS-DAT or SAC in period 1, and patients continued as randomized into a two-way crossover design during periods 2 and 3 where they received niraparib 200 mg/AA 1000 mg once daily as a RS-DAT or SAC. The design was powered on the basis of crossover assessment of RS-DAT versus SAC. During repeated dosing (periods 2 and 3, and extension phase), all patients also received prednisone/prednisolone 5 mg twice daily. Plasma samples were collected for measurement of niraparib and abiraterone plasma concentrations. Statistical assessment of the RS-DAT and LS-DAT versus SAC was performed on log-transformed pharmacokinetic parameters data from periods 2 and 3 (crossover) and from period 1 (parallel), respectively. Additional paired analyses and model-based bioequivalence assessments were conducted to evaluate the similarity between the LS-DAT and SAC. Results For the RS-DAT versus SAC, the 90% confidence intervals (CI) of geometric mean ratios (GMR) for maximum concentration at a steady state (C max,ss ) and area under the plasma concentration–time curve from 0–24 h at a steady state (AUC 0–24h,ss ) were respectively 99.18-106.12% and 97.91-104.31% for niraparib and 87.59-106.69 and 86.91-100.23% for abiraterone. For the LS-DAT vs SAC, the 90% CI of GMR for AUC 0–72h of niraparib was 80.31-101.12% in primary analysis, the 90% CI of GMR for C max,ss and AUC 0–24h ,ss of abiraterone was 85.41-118.34% and 86.51-121.64% respectively, and 96.4% of simulated LS-DAT versus SAC BE trials met the BE criteria...

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PROREPAIR-B: A prospective cohort study of DNA repair defects in metastatic castration resistant prostate cancer (mCRPC)

Cited by 4 publications

References 0 publications

Circulating tumor DNA in advanced prostate cancer: transitioning from discovery to a clinically implemented test

Circulating tumor DNA in advanced prostate cancer: transitioning from discovery to a clinically implemented test

Plasma DNA and Metastatic Castration-Resistant Prostate Cancer: The Odyssey to a Clinical Biomarker Test

Demonstrating Bioequivalence for Two Dose Strengths of Niraparib and Abiraterone Acetate Dual-Action Tablets Versus Single Agents: Utility of Clinical Study Data Supplemented with Modeling and Simulation

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