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NEWS: Andrew Cole Cancer expert doubts claims about prostate cancer trial BMJ 2008; 337: a979 [Full text]

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Prostate Cancer’s Day in the Sun

Gerhardt Attard, Alison H. Reid, David Dearnaley, Johann S. De Bono   (31 July 2008)

Prostate Cancer’s Day in the Sun 31 July 2008
Gerhardt Attard, Clinical Research Fellow The Institute for Cancer Research, The Royal Marsden NHS Foundation Trust, Downs Rd, Sutton, SM2 5PT, Alison H. Reid, David Dearnaley, Johann S. De Bono Send response to journal: Re: Prostate Cancer’s Day in the Sun	The recent publication of the results of our 21-patient phase I study investigating abiraterone acetate in castration-resistant prostate cancer (CRPC) (1) was received very positively by the scientific press (2) and resulted in significant interest from the general media. This has been followed by more critical reports to these media statements (3). While recognizing again that these data are preliminary, we want to emphasize the importance of an immediate paradigm shift required by all physicians from referring to end-stage prostate cancer as "hormone-refractory" or "androgen-independent" disease to acknowledging that a large proportion of these patients continue to have hormone-dependent cancer, and that indeed these cancer cells generate their own hormones. This misnomer has hindered prostate cancer drug development for over 40 years and has previously thwarted the clinical development of secondary hormonal treatments, like the aromatase inhibitors that have been successful in the treatment of breast cancer. We agree that declines in PSA are of limited relevance in this population of patients, particularly in response to a drug targeting androgen-receptor (AR) signaling. We have therefore emphasized in our publication that PSA declines have been associated with radiological regression of soft tissue and bone metastasis, normalization of high lactate dehydrogenase and symptomatic improvement allowing stopping of analgesics, including opiates. We have also seen decrements in the circulating tumor cell count following treatment, which is increasingly being recognized as a potential intermediate endpoint of clinical benefit in multiple cancers. Over the past few years we and others have studied a number of different anti-cancer drugs in this patient population including HER2 targeting drugs, pan-ErbB inhibitors, histone deacetylase inhibitors, anti -angiogenics, a survivin anti-sense and several novel cytotoxics (4). In none of these trials have we observed anything like the biochemical, radiological and, importantly, symptomatic benefit reported with abiraterone acetate. Moreover, the results of our phase I study have been confirmed by a second phase I study in North America and four phase II studies run by our team and several North American investigators. These studies were recently presented at the American Society of Clinical Oncology annual meeting held in Chicago, Illinois (5-7) and will be published over the next year. Although we again emphasize that these results remain preliminary and require confirmation in an ongoing 1180- patient phase III study, they are very encouraging and anticipate that further therapeutic targeting of the AR-signaling axis in CRPC can achieve disease control in a significant proportion of CRPC patients whose prostate cancer has progressed through all currently available hormonal treatments. Nevertheless, while these therapies should not be heralded as a cure for metastatic CRPC, it is clear that our research is leading us closer to an increased understanding of the biology of this disease which, in turn, increases the likelihood of our achieving better long-term control of this fatal disease. Abiraterone now needs to be further evaluated in the adjuvant setting in high risk patients, to evaluate whether it can decrease the risk of recurrence. Moreover, further evaluation of robust biomarkers that can serve as intermediate end-points is urgently required in CRPC therapeutic studies to try and accelerate drug approval by the regulatory authorities. Our phase III study is therefore incorporating the prospective evaluation of whether changes in CTC counts post-treatment can serve as a robust intermediate endpoint for overall survival to accelerate drug development for CRPC (work funded by a Medical Research Council Biomarkers grant). Finally, while we are concerned about raising expectations for prostate cancer sufferers we are also aware that much research is still required to improve the outcome from this common disease. We hope that the publicity generated by these data will have a number of positive outcomes. Firstly, that the intense media interest will lead to rapid accrual to the ongoing phase III study and that the primary endpoint will consequently be reached sooner. Secondly, we hope that increased public awareness of prostate cancer will lead to improved funding into prostate cancer research which currently remains unsatisfactory. The National Cancer Research Institute, UK review in 2003 reported that prostate cancer specific funding was half that of breast cancer despite similar numbers of people dying of each cancer and is also half that of leukaemia funding despite twice as many people dying of prostate cancer (8). Thirdly, we hope that it will now be widely acknowledged by all physicians that CRPC frequently remains a hormone-dependent disease and that the development of further hormonal manipulation strategies like this may impact the quality of care and lives of our patients. References 1. Attard G, Reid A, Yap T, Raynaud F, Dowsett M, Settatree S, et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer (CRPC) commonly remains hormone driven. Journal of Clinical Oncology. In press 2008. 2. Raghavan D, Klein EA. Prostate Cancer: Moving Forward by Reinventing the Wheel...But This Time It Is Round. J Clin Oncol 2008. 3. Cole A. Cancer expert doubts claims about prostate cancer trial. Bmj 2008;337:a979. 4. Attard G, Sarker D, Reid A, Molife R, Parker C, de Bono JS. Improving the outcome of patients with castration-resistant prostate cancer through rational drug development. Br J Cancer 2006;95(7):767-74. 5. Danila DC RD, Morris MJ, Slovin SF, Schwartz LH, Farmer K, Anand A, Haqq C, Fleisher M, Scher HI. Abiraterone acetate and prednisone in patients (Pts) with progressive metastatic castration resistant prostate cancer (CRPC) after failure of docetaxel-based chemotherapy. J Clin Oncol 2008;26((May 20 suppl; abstr 5019)). 6. Ryan C SM, Rosenberg JE, Lin AM, Taplin M, Kantoff PW, Huey V, Kim J, Small EJ. Impact of prior ketoconazole therapy on response proportion to abiraterone acetate, a 17-alpha hydroxylase C17,20-lyase inhibitor in castration resistant prostate cancer (CRPC). J Clin Oncol 2008;26((May 20 suppl; abstr 5018)). 7. De Bono JS AG, Reid AH, Parker C, Dowsett M, Mollife R, Yap TA, Molina A, Lee G, Dearnaley D. Anti-tumor activity of abiraterone acetate (AA), a CYP17 inhibitor of androgen synthesis, in chemotherapy naive and docetaxel pre-treated castration resistant prostate cancer (CRPC). J Clin Oncol 2008;26((May 20 suppl; abstr 5005)). 8. O'Toole L, Nurse P, Radda G. An analysis of cancer research funding in the UK. Nat Rev Cancer 2003;3(2):139-43. Competing interests: Abiraterone acetate was discovered at The Institute of Cancer Research, which therefore has a commercial interest in the development of this agent. Dr De Bono is a paid employee of the Institute of Cancer Research. Dr de Bono has served as an unpaid consultant for Cougar Biotechnology. The authors are employees of The Section of Medicine which is supported by a Cancer Research UK program grant and an Experimental Cancer Medical Centre (ECMC) grant from Cancer Research UK and the Department of Health. The authors were also supported by the Medical Research Council; the Prostate Cancer Research Foundation and the Royal Marsden Hospital General Research Council Fund.