Simon J Crabb1, Syed Hussain2, Eileen Soulis3, Samantha Hinsley3, Laura Dempsey3, Avril Trevethan3, YeePei Song4, Jim Barber5, John Frew6, Joanna Gale7, Guy Faust8, Susannah Brock9, Ursula McGovern10, Omi Parikh11, Deborah Enting12, Santhanam Sundar13, Gihan Ratnayake14, Kathryn Lees15, Alison J Birtle16, Thomas Powles17, Robert J Jones3. 1. Southampton Experimental Cancer Medicine Centre, University of Southampton, Southampton, United Kingdom. 2. University of Sheffield and Sheffield Teaching Hospitals, Sheffield, United Kingdom. 3. CRUK Glasgow Clinical Trials Unit, University of Glasgow, Glasgow, United Kingdom. 4. The Christie NHS Foundation Trust, Manchester, United Kingdom. 5. Velindre Cancer Centre, Cardiff, United Kingdom. 6. Northern Centre for Cancer Care, Newcastle upon Tyne, United Kingdom. 7. Portsmouth Hospitals NHS Trust, Portsmouth, United Kingdom. 8. Leicester Royal Infirmary NHS Trust, Leicester, United Kingdom. 9. Dorset Cancer Centre, University Hospitals Dorset NHS Foundation Trust, Poole, United Kingdom. 10. University College Hospital, University College London Hospitals NHS Foundation Trust, London, United Kingdom. 11. Royal Blackburn Teaching Hospital, East Lancashire Hospitals NHS Trust, Blackburn, United Kingdom. 12. Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom. 13. Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom. 14. Musgrove Park Hospital, Taunton, United Kingdom. 15. Maidstone and Tunbridge Wells NHS Trust, Maidstone, United Kingdom. 16. Rosemere Cancer Centre, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, United Kingdom. 17. St Bartholomew's Hospital, London, United Kingdom.
Abstract
PURPOSE: A 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. METHODS: DRD 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 α for this signal-seeking trial. PFS (RECIST 1.1) was compared between trial arms, by intention to treat, within a Cox model. RESULTS: Out 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. CONCLUSION: Maintenance 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.
PURPOSE: A 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. METHODS: DRD 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 α for this signal-seeking trial. PFS (RECIST 1.1) was compared between trial arms, by intention to treat, within a Cox model. RESULTS: Out 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. CONCLUSION: Maintenance 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.
Authors: Peter C Black; Nazanin Fallah-Rad; Andrew Loblaw; Elie Kassouf; Mira Keyes; Naveen S Basappa; Anand Swaminath Journal: Can Urol Assoc J Date: 2022-09 Impact factor: 2.052