PracticeUpdate: Haematology & Oncology | Vol 1.No.3 - 2016

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PROSTATE

EXPERT OPINION Proteosome inhibitors in advanced castrate-resistant prostate cancer Interview with Guru Sonpavde, MD

EDITORIAL Managing Editor Anne Neilson anne.neilson@elsevier.com Editor Carolyn Ng carolyn.ng@elsevier.com Designer Jana Sokolovskaja j.sokolovskaja@elsevier.com Medical Advisor Dr Barry M Dale Consultant Haematologist, Medical Oncologist

Dr Sonpavde, Associate Professor of Medicine, UAB School of Medicine in Alabama, discusses the novel proteasome inhibitors and where this class of drug would fit in the spectrum of treatment for advanced prostate cancer.

Dr Haffizulla: I know that you are the principal investigator for an upcom- ing clinical trial, and probably the date will mature in the next couple of years or months. The trial concerns proteasome inhibitors, especially

carfilzomib and its place in the spec- trum of treatment in prostate cancer. Can you tell me a little bit more about this particular class of drugs? Dr Sonpavde: This is a novel class of compounds to be looked at in ad- vanced castrate-resistant prostate cancer. Proteasome inhibitors, of course, are widely used in multiple myeloma, or haematologic malig- nancy. There is rationale to look at them in advanced prostate cancer. More than a decade ago, bortezomib was the first in class proteasome in- hibitor also approve in myeloma. It was looked at in a phase 1 trial that included solid tumours, and there was deep activity in a small subset of patients with advanced castrate- resistant prostate cancer. That

included tumour tissue responses, regressions, and PSA declines. That was a small subset, but the responses were deep. So we believe that there might be even better activity with carfilzomib, which is a more potent irreversible proteasome inhibitor, in patients with this disease. We have a phase 2 trial ongoing looking at this. Dr Haffizulla: Where do you think that would fit into the spectrum of treatment for advanced prostate cancer, specifically castrate-resistant prostate cancer? Dr Sonpavde: One of the things that we are still learning is that, despite all of the agents that are out now, including enzalutamide and abira- terone, which are novel androgen pathway-inhibiting drugs, they’re active, but there is a ton of cross-re- sistance. The patients who progress on abiraterone, or enzalutamide, when switched to the other drug, don’t have a huge response rate. The response rate is in the 20% to 30% range. So we need new classes of agents for these patients who are progressing after these novel agents, because of the cross-resistance. There could be a big draw for a new class of agents in these patients who progress after abiraterone, or enzalutamide, or both. There could be a big draw for a new class of agents in these patients who progress after abiraterone, or enzalutamide, or both.

SALES Commercial Manager Fleur Gill fleur.gill@elsevier.com

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View the full interview with Dr Guru Sonpavde

JOURNAL SCAN Conventional vs hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer The Lancet Oncology Take-home message • This phase 3 noninferiority study enrolled 3216 men with localised prostate cancer who were randomised 1:1:1 to receive conventional radiotherapy (74 Gy in 37 fractions over 7.4 weeks) or one of two hypofractionated schedules (60 Gy in 20 fractions over 4 weeks or 57 Gy in 19 fractions over 3.8 weeks). At 5 years, the proportion of patients who were clinically or biochemically failure-free were comparable between patients receiving 60 Gy and the conventional 74 Gy (90.6% and 88.3%, respectively), and the two schedules were noninferior; however, 57 Gy (85.9 % of patients failure-free) was not noninferior to 74 Gy. Side effects were similar between conventional and hypofractionated treatment groups based on clinician- and patient-reported outcomes. • The authors recommend hypofractionated radiotherapy at 60 Gy over 20 fractions as a new standard of care for radiotherapy in patients with localised prostate cancer given that it is noninferior to the conventional 74 Gy in 37 fractions.

Abstract BACKGROUND Prostate cancer might have high radiation-fraction sensitivity that would give a therapeutic advan- tage to hypofractionated treatment. We present a pre-planned analysis of the efficacy and side-effects of a ran- domised trial comparing conventional and hypofractionated radiotherapy after 5 years follow-up. METHODS CHHiP is a randomised, phase 3, non-inferiority trial that recruited men with localised prostate cancer (pT1b- T3aN0M0). Patients were randomly assigned (1:1:1) to conventional (74 Gy delivered in 37 fractions over 7.4 weeks) or one of two hypofractionated sched- ules (60 Gy in 20 fractions over 4 weeks or 57 Gy in 19 fractions over 3·8 weeks) all delivered with intensity-modulated techniques. Most patients were given radiotherapy with 3–6 months of neo- adjuvant and concurrent androgen suppression. Randomisation was by computer-generated random permuted blocks, stratified by National Compre- hensive Cancer Network (NCCN) risk group and radiotherapy treatment centre, and treatment allocation was not masked. The primary endpoint was time to biochemical or clinical failure; the critical hazard ratio (HR) for non- inferiority was 1.208. Analysis was by intention to treat. Long-term follow-up continues. FINDINGS Between Oct 18, 2002, and June 17, 2011, 3216 men were enrolled from 71 centres and randomly assigned (74 Gy group, 1065 patients; 60 Gy group, 1074 patients; 57 Gy group, 1077 patients). Median follow-up was 62.4

and bladder adverse events was 13.7% (111 events) and 9.1% (66 events) in the 74 Gy group, 11.9% (105 events) and 11.7% (88 events) in the 60 Gy group, 11.3% (95 events) and 6.6% (57 events) in the 57 Gy group, respectively. No treatment- related deaths were reported. INTERPRETATION Hypofractionated radio- therapy using 60 Gy in 20 fractions is non-inferior to conventional fractiona- tion using 74 Gy in 37 fractions and is recommended as a new standard of care for external-beam radiotherapy of localised prostate cancer. Conventional versus hypofraction- ated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial . Lancet Oncol 2016;17:1047–1060, Dearnaley D, Syndikus I, Mossop H, et al.

months (IQR 53.9–77.0). The propor- tion of patients who were biochemical or clinical failure free at 5 years was 88.3% (95% CI 86.0–90.2) in the 74 Gy group, 90.6% (88.5–92.3) in the 60 Gy group, and 85.9% (83.4–88.0) in the 57 Gy group. 60 Gy was non-inferior to 74 Gy (HR 0.84 [90% CI 0.68–1.03], pNI=0.0018) but non-inferiority could not be claimed for 57 Gy compared with 74 Gy (HR 1.20 [0.99–1.46], pNI=0.48). Long-term side-effects were similar in the hypofractionated groups compared with the conventional group. There were no significant differences in either the proportion or cumulative incidence of side-effects 5 years after treatment using three clinician-reported as well as patient-reported outcome measures. The estimated cumulative 5 year inci- dence of Radiation Therapy Oncology Group (RTOG) grade 2 or worse bowel

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