A Randomized, Double-Blind, Biomarker-Selected, Phase II Clinical Trial of Maintenance Poly ADP-Ribose Polymerase Inhibition With Rucaparib Following Chemotherapy for Metastatic Urothelial Carcinoma

被引：24

作者：

Crabb, Simon J. ^{[1
]}

Hussain, Syed ^{[2
,3
]}

Soulis, Eileen ^{[4
]}

Hinsley, Samantha ^{[4
]}

Dempsey, Laura ^{[4
]}

Trevethan, Avril ^{[4
]}

Song, YeePei ^{[5
]}

Barber, Jim ^{[6
]}

Frew, John ^{[7
]}

Gale, Joanna ^{[8
]}

Faust, Guy ^{[9
]}

Brock, Susannah ^{[10
]}

McGovern, Ursula ^{[11
]}

Parikh, Omi ^{[12
]}

Enting, Deborah ^{[13
]}

Sundar, Santhanam ^{[14
]}

Ratnayake, Gihan ^{[15
]}

Lees, Kathryn ^{[16
]}

Birtle, Alison J. ^{[17
]}

Powles, Thomas ^{[18
]}

Jones, Robert J. ^{[4
]}

机构：

[1] Univ Southampton, Southampton Expt Canc Med Ctr, Southampton, Hants, England

[2] Univ Sheffield, Sheffield, S Yorkshire, England

[3] Sheffield Teaching Hosp, Sheffield, S Yorkshire, England

[4] Univ Glasgow, CRUK Glasgow Clin Trials Unit, Glasgow, Lanark, Scotland

[5] Christie NHS Fdn Trust, Manchester, Lancs, England

[6] Velindre Canc Ctr, Cardiff, Wales

[7] Northern Ctr Canc Care, Newcastle Upon Tyne, Tyne & Wear, England

[8] Portsmouth Hosp NHS Trust, Portsmouth, Hants, England

[9] Leicester Royal Infirm NHS Trust, Leicester, Leics, England

[10] Univ Hosp Dorset NHS Fdn Trust, Dorset Canc Ctr, Poole, Dorset, England

[11] Univ Coll London Hosp NHS Fdn Trust, Univ Coll Hosp, London, England

[12] East Lancashire Hosp NHS Trust, Royal Blackburn Teaching Hosp, Blackburn, Lancs, England

[13] Guys & St Thomas NHS Fdn Trust, London, England

[14] Nottingham Univ Hosp NHS Trust, Nottingham, England

[15] Musgrove Pk Hosp, Taunton, Somerset, England

[16] Maidstone & Tunbridge Wells NHS Trust, Maidstone, Kent, England

[17] Lancashire Teaching Hosp NHS Fdn Trust, Rosemere Canc Ctr, Preston, Lancs, England

[18] St Bartholomews Hosp, London, England

来源：

JOURNAL OF CLINICAL ONCOLOGY | 2023年 / 41卷 / 01期

关键词：

CISPLATIN-BASED CHEMOTHERAPY; OVARIAN-CARCINOMA; BLADDER-CANCER; OPEN-LABEL; THERAPY; MULTICENTER; PLACEBO; SURVIVAL; DEFECTS;

D O I：

10.1200/JCO.22.00405

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

PURPOSEA DNA repair deficiency (DRD) phenotype exists within a subset of metastatic urothelial carcinomas (mUC) predicting benefit from platinum-based chemotherapy. We tested switch maintenance therapy with the poly ADP-ribose polymerase inhibitor rucaparib, following chemotherapy, for DRD biomarker-positive mUC.METHODSDRD biomarker-positive mUC patients, within 10 weeks of chemotherapy, and without cancer progression, were randomly assigned (1:1) to maintenance rucaparib 600 mg twice a day orally, or placebo, until disease progression. The primary end point was progression-free survival (PFS). Statistical analysis targeted a hazard ratio of 0.5 with a 20% one-sided alpha for this signal-seeking trial. PFS (RECIST 1.1) was compared between trial arms, by intention to treat, within a Cox model.RESULTSOut of 248 patients, 74 (29.8%) were DRD biomarker-positive and 40 were randomly assigned. A total of 12 (60%) and 20 (100%) PFS events occurred in the rucaparib and placebo arms, respectively (median follow-up was 94.6 weeks in those still alive). Median PFS was 35.3 weeks (80% CI, 11.7 to 35.6) with rucaparib and 15.1 weeks (80% CI, 11.9 to 22.6) with placebo (hazard ratio, 0.53; 80% CI, 0.30 to 0.92; one-sided P = .07). In the safety population (n = 39) treatment-related adverse events were mostly low grade. Patients received a median duration of 10 rucaparib or six placebo cycles on treatment. Treatment-related adverse events (all grades) of fatigue (63.2% v 30.0%), nausea (36.8% v 5.0%), rash (21.1% v 0%), and raised alanine aminotransferase (57.9% v 10%) were more common with rucaparib.CONCLUSIONMaintenance rucaparib, following platinum-based chemotherapy, extended PFS in DRD biomarker-selected patients with mUC and was tolerable. Further investigation of poly ADP-ribose polymerase inhibition in selected patients with mUC is warranted.

引用

页码：54 / +

页数：13

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