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Sarker, S-J

Shamash, J

British Journal of Cancer

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Comment on 'Anti-tumour activity of abiraterone and diethylstilboestrolwhen administered sequentially to men with castration-resistant prostatecancer'.Shamash, J; Sarker, SJ     2014. Cancer Research UK  For additional information about this publication click this link.http://qmro.qmul.ac.uk/xmlui/handle/123456789/10336   Information about this research object was correct at the time of download; we occasionallymake corrections to records, please therefore check the published record when citing. Formore information contact scholarlycommunications@qmul.ac.ukComment on ‘Anti-tumour activity ofabiraterone and diethylstilboestrol whenadministered sequentially to men withcastration-resistant prostate cancer’J Shamash*,1 and S-J Sarker21St Bartholomew’s Hospital, 7th Floor, Gloucester House, Little Britain, UK and 2Centre for Experimental Cancer Medicine, QueenMary University of London, London, UKOmlin et al (2013) report the anti-tumour activity of diethylstilbestrol(DS) and abiraterone (AA) in castration-resistant prostate cancer andsuggest substantial activity of AA in DS pretreated patients. Theirretrospective review includes patients who were post docetaxel as wellas those who were chemotherapy naive. We feel that the additionalactivity of AA may have been overstated. Abiraterone is alwayscombined with a corticosteroid – and therefore the comparison isbetween AA and a corticosteroid vs DS and a corticosteroid. Most ofthe patients in the series described by Omlin et al (2013) received DSwithout a corticosteroid. In the paper by Ryan et al (2013) mediantime to progression (TTP) was doubled when AA and prednisonewas compared with prednisone alone (11.1 vs 5.6 months). When thecombination of dexamethasone and DS was compared to dex-amethasone alone, a similar effect was seen (8.6 vs 4.5 months) inchemotherapy-naive patients (Shamash et al, 2011), see table below.Dexamethasone with deferred DS vs dex-amethasone and DS (Shamash et al,2011)Prednisone vs AA andprednisone (Ryan et al,2013)Randomisation Yes YesDouble blind No YesECOG PS 0–3 0–1PSA progression PCWG1 PCWG2Patients All chemo naı¨ve All chemo naivePFS (rad) Not stated 16.5 vs 8.3Median TTP (PSA) All: 8.5, dexamethasone alone: 4.5, DdS*(overall): 8.4, DS: 8.6Prednisone: 5.6 AA/pre-dnisone: 11.1Median overall survival (OS) All: 19.1 (95% CI: 16.8–21.4), DdS: 18.8,DS: 19.4(33% went on to receive chemotherapy)27.2 vs 427.2Median OS (PS¼ 0) All: 28.7, DdS: 26.2,DS: 38.1427.2HR for survival 0.79 (0.57–1.08): DS vs DdS 0.75 (0.61–0.93)HR for survival (PS¼ 0) 0.63 (0.33, 1.2) 0.71 (0.55, 0.92)PSA decline X50% All: 66%, dexamethasone alone: 50%, DS68%Prednisone 24% vs AA/prednisone 62%DdS* DS was added when the patient progressed.We feel that some of the responses described could alsobe explained by the fact that DS was given before docetaxel andAA after. There is evidence that chemotherapy following failure ofa hormone therapy allows that treatment to work again whenpatients are rechallenged with the same hormone therapy.We have reviewed our data on patients who went on to receiveDS and dexamethasone followed on progression by AA andprednisolone. We have identified 12 patients who had DS anddexamethasone immediately prior to AA and prednisolone. Elevenhad prior treatment with docetaxel. Five out of 12 had a 50% PSAresponse to DS. Progression-free survival was 7.0 months (range3.6–8.7), for the whole group it was 3.4 months (range 1.1–8.7).For subsequent AA and prednisolone only one patient responded(PFS 8.1 months). The overall PFS was 1.8 months (range 0.6–8.1).For the 11 who received docetaxel, 10 had prior DS. Five outof 10 had a 50% PSA response with a PFS of 7.0 months(range 1.0–15.0). For this group, overall PFS was 5.75 months(range 1–15). Four out of these five subsequently re-respondedfollowing docetaxel.This supports our view that many patients who respond tohormone therapy prechemotherapy will subsequently respond tothe same hormonal therapy afterwards (Shamash et al, 2008) andthat cross-resistance between AA and DS when combined withsteroids may be much greater than has been suggested.REFERENCESOmlin A, Pezaro CJ, Zaidi S, Lorente1 D, Mukherji1 D, Bianchini1 D,Ferraldeschi1 R, Sandhu1 S, Dearnaley D, Parker C, As NV,de Bono1 JS, Attard C (2013) Antitumour activity of abirateroneand diethylstilboestrol when administered sequentially to menwith castration-resistant prostate cancer. Br J Cancer 109: 1079–1084.Ryan CJ, Smith MR, De Bono JS, Molina A, Logothetis CJ, de Souza Paul,Fizazi K, Mainwaring P, Piulats JM (2013) Abiraterone in metastatic prostatecancer without previous chemotherapy. N Engl J Med 368: 138–148.Shamash J, Davies A, Ansell W, Mcfaul S, Wilson P, Oliver T, Powles T (2008)A phase II study investigating the re-induction of endocrine sensitivityfollowing chemotherapy in androgen-independent prostate cancer.Br J Cancer 98(1): 22–24.British Journal of Cancer (2014) 110, 266–267 | doi: 10.1038/bjc.2013.736*Correspondence: Dr J Shamash; E-mail: jonathan.shamash@bartshealth.nhs.ukPublished online 3 December 2013& 2014 Cancer Research UK. All rights reserved 0007 – 0920/14BRITISH JOURNAL OF CANCER Letters to the Editor266 www.bjcancer.com |DOI:10.1038/bjc.2013.736Shamash J, Powles T, Sarker SJ, Protheroe A, Mithal N, Mills R, Beard R,Wilson P, Tranter N, O’Brien N, McFaul S, Oliver T (2011) A multi-centrerandomised phase III trial of Dexamethasone vs Dexamethasone anddiethylstilbestrol in castration-resistant prostate cancer: immediate vsdeferred Diethylstilbestrol. Br J Cancer 104: 620–628.This work is licensed under the Creative CommonsAttribution-NonCommercial-Share Alike 3.0 UnportedLicense. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/Reply: ‘Comment on Anti-tumour activity ofabiraterone and diethylstilboestrol whenadministered sequentially to men withcastration-resistant prostate cancer’A Omlin1, C J Pezaro1, S Zaidi2, D Lorente1, D Mukherji1, D Bianchini1, R Ferraldeschi1, S Sandhu1,D Dearnaley2, C Parker3, N Van As4, J S de Bono1 and G Attard*,11Prostate Cancer Targeted Therapy Group and Drug Development Unit, Section of Medicine, The Royal Marsden NHSFoundation Trust and The Institute of Cancer Research, Downs Road, Sutton, Surrey SM2 5PT, UK; 2Academic Urology Unit,Sutton, The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Downs Road, Sutton, Surrey, UK;3Academic Urology Unit, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey, UK and 4Academic Urology Unit,The Royal Marsden NHS Foundation Trust, Fulham Road, Chelsea, London, UKSir,We thank Shamash and Sarker for their interest in our recentarticle (Omlin et al, 2013). They make three comments: first, thatthe activity of diethylstilboestrol (DES) when combined with acorticosteroid such as dexamethasone (D) is increased compared toDES alone; second, that chemotherapy may re-induce sensitivity toa hormonal agent; finally, their experience in 11 patients whoreceived the sequence of docetaxel followed by DES and D andthen abiraterone acetate (AA) and prednisone. In this setting theactivity of AA was limited, as indicated by a median progression-free survival (PFS) of 1.8 months (range 0.6–8.1).We wish to clarify that we did not report any data onDES activity prior to treatment with AA because it was not possibleto get complete DES activity data for patients treated outside of ourinstitution. We therefore only reported duration of DES treatment.Our large institutional experience with single-agent DES andaspirin in 231 men with castration resistant prostate cancer(CRPC) showed a median time to PSA progression of 4.6 months,X50% PSA declines in 28.9% of patients and a VTE rate of 9.9%(Wilkins et al, 2012). We acknowledge that the activity of DESmay be modestly higher when it is combined with D, whichhas been shown to have single-agent anti-tumour activity in menwith castration-resistant prostate cancer, although there is littleevidence that this therapeutic manoeuvre imparts significantclinical benefit (Venkitaraman et al, 2008). The comparison ofDES plus D with D alone by Shamash et al (2011) is interesting butraised concerns that DES is associated with a major risk of serioustoxicity, unlike AA, with veno-thromboembolic events (VTEs) in22% of patients despite prophylactic treatment with aspirin. Giventhat AA provides overall survival benefit in Phase III trials, AA is apreferable treatment to DES for CRPC (de Bono et al, 2011;Ryan et al, 2013). Indeed we believe that there may nowbe little merit in administering DES to patients sufferingfrom CRPC.The hypothesis that chemotherapy may induce sensitivity toendocrine agents is also intriguing. However, clinical trials of AAand enzalutamide have all reported higher response rates pre-chemotherapy than afterwards, suggesting overlapping mechan-isms of resistance (Scher et al, 2010, 2012; de Bono et al, 2011;Ryan et al, 2013). The study referenced by Shamash et al (2008) didnot utilise taxanes (that through their postulated disruption of ARsignalling may be associated with cross-resistance with endocrinetreatments) and allowed cessation of androgen deprivation with49% of patients having non-castrate levels of testosterone at theBritish Journal of Cancer (2014) 110, 267–268 | doi: 10.1038/bjc.2013.737*Correspondence: Dr G Attard; E-mail: gerhardt.attard@icr.ac.ukPublished online 3 December 2013& 2014 Cancer Research UK. All rights reserved 0007 – 0920/14Letters to the Editor BRITISH JOURNAL OF CANCERwww.bjcancer.com |DOI:10.1038/bjc.2013.737 267

Comment on 'Anti-tumour activity of abiraterone and diethylstilboestrol when administered sequentially to men with castration-resistant prostate cancer'

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Comment on 'Anti-tumour activity of abiraterone and diethylstilboestrol when administered sequentially to men with castration-resistant prostate cancer'

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