Competing interests
`The authors declare no competing interests.
`
`1. Garbe, C., Eigentler, T. K., Keilholz, U.,
`Hauschild, A. & Kirkwood, J. M. Systematic
`review of medical treatment in melanoma:
`current status and future prospects. Oncologist
`16, 5–24 (2011).
`2. Atkins, M. B. et al. High‑dose recombinant
`interleukin 2 therapy for patients with
`metastatic melanoma: analysis of 270 patients
`treated between 1985 and 1993. J. Clin. Oncol.
`17, 2105–2116 (1999).
`3. Schwartzentruber, D. J. et al. gp100 peptide
`vaccine and interleukin‑2 in patients with
`advanced melanoma. N. Engl. J. Med. 364,
`2119–2127 (2011).
`4. Hodi, F. S. et al. Improved survival with
`ipilimumab in patients with metastatic
`melanoma. N. Engl. J. Med. 363, 711–723
`(2010).
`
`5. Robert, C. et al. Ipilimumab plus dacarbazine
`for previously untreated metastatic melanoma.
`N. Engl. J. Med. 364, 2517–2526 (2011).
`6. Davies, H. et al. Mutations of the BRAF gene in
`human cancer. Nature 471, 949–954 (2002).
`7. Ribas, A. et al. BRIM‑2: an open‑label,
`multicenter phase II study of vemurafenib in
`previously treated patients with BRAF V600E
`mutation‑positive metastatic melanoma
`[abstract]. J. Clin. Oncol. 29 (Suppl.), a8509
`(2011).
`8. Chapman, P. B. et al. Improved survival with
`vemurafenib in melanoma with BRAF V600E
`mutation. N. Engl. J. Med. 364, 2507–2516
`(2011).
`9. Kwon, E. J., Kish, L. S. & Jaworsky, C. The
`histologic spectrum of epithelial neoplasms
`induced by sorafenib. J. Am. Acad. Dermatol.
`61, 522–527 (2009).
`10. Smalley, K. S. & Sondak, V. K. Melanoma—an
`unlikely poster child for personalized cancer
`therapy. N. Engl. J. Med. 363, 876–878 (2010).
`
`COMBINATION THERAPY
`
`Abiraterone prolongs survival
`in metastatic prostate cancer
`
`Oliver Sartor
`
`Abiraterone plus prednisone prolongs overall survival relative to
`prednisone alone in patients with metastatic castration‑resistant prostate
`cancer who have disease progression after treatment with docetaxel.
`The survival gain observed in this pivotal trial is accomplished with
`few adverse events and conclusively demonstrates that patients with
`castration levels of serum testosterone remain sensitive to additional
`hormonal manipulation.
`Sartor, O. Nat. Rev. Clin. Oncol. 8, 515–516 (2011); published online 2 August 2011;
`doi:10.1038/nrclinonc.2011.111
`
`The recent article by de Bono and colleagues1
`describing an improvement in overall sur‑
`vival for patients treated in the phase III trial
`(COU‑AA‑301) with abiraterone plus pred‑
`nisone, dramatically alters our view of hor‑
`monal treatment in advanced‑stage prostate
`cancer. This trial enrolled 1,195 men with
`metastatic castration‑ resistant prostate
`cancer (CRPC) with disease progression
`despite previous therapy with docetaxel.
`Patients were randomly assigned to receive
`abiraterone plus prednisone or placebo
`plus prednisone; the primary end point was
`overall survival. The trial was terminated
`early by the data‑monitoring committee
`as a consequence of a pre‑planned interim
`efficacy analysis. At the time the trial
`was stopped, the median overall survival was
`14.8 months in the abiraterone group versus
`10.9 months in the control group (hazard
`ratio [HR] = 0.65, P <0.0001). The therapy
`was well tolerated and now, as a conse‑
`quence of this pivotal trial, abiraterone is
`
`Practice point
`
`Abiraterone is the first hormonal
`agent to prolong survival in metastatic
`castration‑resistant prostate cancer and
`it achieves this goal with a moderate
`adverse‑event profile
`
`approved by the FDA in the post‑docetaxel
`metastatic CRPC setting.
`Since the Nobel Prize‑winning work of
`Huggins and Hodges published in 1941,2 it
`has been well accepted that lowering testo‑
`sterone to castration levels by orchiectomy
`or treatment with estrogens was effective in
`the treatment of metastatic prostate cancer.
`Since then, advances in hormonal therapy for
`this disease have been important but limited.
`In the 1980s, luteinizing hormone‑releasing
`hormone (LHRH) agonists—which dramati‑
`cally lower testo sterone to levels equivalent
`to those obtained with orchiectomy—were
`introduced in the clinic and men could avoid
`
`NEWS & VIEWS
`
`both the psycho logical issues of surgical
`orchiectomy and the side effects of estrogens
`(such as deep vein thrombosis and pulmo‑
`nary embolism, and other thrombo embolic
`complica tions). Later, some—but not all
`—trials with anti androgens demon strated a
`modest advantage in overall survival when
`used in combination with medical or surgi‑
`cal castra tion. Until 2004, however, no trial
`had demon strated an increase in overall
`survival in patients with castration levels
`of testo sterone. In that year, docetaxel plus
`prednisone and docetaxel plus estra mustine
`were shown to prolong overall survival com‑
`pared with mitoxantrone plus prednisone in
`patients with metastatic ‘hormone‑refractory’
`prostate cancer.4,5
`The past 2 years have seen an increasing
`activity in the development of therapies that
`target metastatic prostate cancer recurring
`after initial androgen deprivation. After
`docetaxel, Sipuleucel‑T was the second
`agent shown to prolong overall survival,6
`followed by cabazitaxel.7 Abiraterone was
`the fourth agent,1 and now a fifth agent
`(alpharadin)8 has joined the group (Table 1).
`After many years of futile effort, the recent
`progress in prolonging survival is stunning
`for those long involved in the field.
`The evidence that castrated patients can
`have a second‑line hormonal treatment
`—abiraterone—that prolongs overall sur‑
`vival disrupts the long‑standing dogma that
`these patients are ‘hormone‑refractory’. In
`fact, on the contrary, it seems that patients
`relapsing after initial androgen deprivation
`are extremely sensitive to concentrations
`of androgens previously thought insignifi‑
`cant. In light of this observation, the term
`‘hormone‑refractory’ is no longer justified
`and ‘castration‑resistant’ is now confirmed
`as the appropriate term because CRPC does
`not imply sensitivity or resistance to hor‑
`monal therapy, only that the prostate cancer
`has progressed after castration.
`Discarding the ‘hormone‑refractory’
`concept is a conceptual breakthrough that
`has far‑reaching implications. First and
`foremost, the androgen–androgen recep‑
`tor (AR) axis remains a validated target in
`CRPC, even when serum levels of testo‑
`sterone are in the castration range. This
`paves the way for a variety of new strat‑
`egies, some of which (blocking AR with the
`antagonist MDV3100, and inhibiting andro‑
`gen synthesis with the inhibitor TAK‑700)
`are now in phase III trials. More therapies
`targeting the androgen–AR axis are on
`their way, with particularly interesting
`compounds such as ARN‑509, TOK‑001,
`
`NATURE REVIEWS | CLINICAL ONCOLOGY
`
`VOLUME 8 | SEPTEMBER 2011 | 515
`
`© 2011 Macmillan Publishers Limited. All rights reserved
`
`WCK1042
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`
`

`
`NEWS & VIEWS
`
`Table 1 | Phase III trials with a prolongation of OS (primary end point) in metastatic CRPC
`
`Regimen
`
`Median OS (months) HR
`
`Trial
`
`TAX3275*
`
`Year
`
`2004
`
`SWOG 99164*
`
`2004
`
`IMPACT6‡
`
`2010
`
`TROPIC7
`
`2010
`
`COU‑AA‑3011§
`
`2011
`
`Docetaxel + prednisone
`vs mitoxantrone + prednisone
`
`Docetaxel + estramustine
`vs mitoxantrone + prednisone
`
`Sipuleucel‑T and ‘unactivated’
`antigen‑presenting cells
`
`Cabazitaxel + prednisone
`vs mitoxantrone + prednisone
`
`Abiraterone + prednisone
`vs placebo + prednisone
`
`18.9 vs 16.5
`
`17.5 vs 15.6
`
`25.8 vs 21.7
`
`15.1 vs 12.7
`
`14.8 vs 10.9
`
`0.76
`
`0.80
`
`0.78
`
`0.70
`
`0.65
`
`0.70
`
`ALSYMPCA8§
`
`Unpublished
`
`Radium‑223 + best supportive care
`vs placebo + best supportive care
`
`14.0 vs 11.2
`
`*SWOG 9916 and TAX327 trials used first‑line chemotherapy. ‡IMPACT trial was carried out in asymptomatic or minimally
`symptomatic patients without visceral metastases. §TROPIC and COU‑AA‑301 trials were conducted in patients who had
`received docetaxel. The Radium‑223 trial was conducted in patients considered ‘unsuitable’ for chemotherapy without
`visceral metastases. Abbreviations: CRPC, castration‑resistant prostate cancer; HR, hazard ratio; OS, overall survival.
`
`and more‑selective inhibitors of steroid
`17‑α‑hydroxylase/17,20 lyase (CYP17) such
`as VT‑464 (Viamet Pharmaceuticals, NC,
`USA). The trial led by de Bono et al.1 was
`conducted in a post‑docetaxel metastatic
`CRPC setting. However, there is no reason
`to believe that activity of abiraterone will be
`restricted to these patients, and a current
`trial of abiraterone in a pre‑docetaxel
`metastatic CRPC setting is expected to be
`reported later this year.
`Recent updates of the abiraterone trial
`have revealed important new information
`that was not included in the original article.
`First, reported pain was markedly reduced
`in the abiraterone plus prednisone arm.9
`Second, preliminary reports indicate that
`circulating tumors cells (CTCs)—a novel
`biomarker indicative of poor prognosis
`—were reduced in the experimental arm
`and that a combination of levels of lactate
`dehydrogenase (LDH) and CTCs at baseline
`and changes in these levels after treatment
`may predict survival, independently of
`therapy, in patients with an elevated base‑
`line CTC count. These data have important
`potential implications for the use of bio‑
`markers and patient reported outcomes in
`future trials that attempt to meet regulatory
`standards. Given the current multiplicity of
`agents shown to be effective in metastatic
`CRPC, it will be challenging to approve
`
`new drugs if overall survival persists as the
`primary end point.
`Before the post‑abiraterone enthusiasm
`becomes irrational, it is important to note
`that time to radiographic progression in the
`trial by de Bono et al.1 was relatively modest.
`Median time to radiographic progression
`was 5.6 months in the abiraterone arm. The
`time to progression measured by prostate‑
`specific antigen (PSA), seems artificially
`long in both arms of the study, perhaps as
`a consequence of the relatively prolonged
`PSA testing interval (every 3 months). We
`note that the median time to PSA progres‑
`sion was 6.6 months in the prednisone
`arm whereas, in another trial conducted in
`patients with metastatic CRPC with disease
`progression after treatment with docetaxel
`(TROPIC), the combination of prednisone
`and mitoxantrone yielded a time to PSA
`progression of 3.1 months.7 In conclu‑
`sion, although abiraterone is an effective
`and relatively well tolerated agent, further
`progress is needed to optimize treatments
`for patients with metastatic CRPC. The next
`step is test this agent in earlier stages of the
`disease and to combine it with other agents
`that have demonstrated activity. I suspect
`that only combination therapy will result
`in the truly dramatic results that clinicians
`expect for patients with advanced‑stage
`prostate cancer.
`
`Department of Medicine and Urology, Tulane
`Cancer Center, Tulane University School of
`Medicine, 1430 Tulane Avenue, New Orleans,
`LA 70112, USA.
`osartor@tulane.edu
`
`Competing interests
`O. Sartor declares associations with the following
`companies: Algeta, Bellicum, Centocor Biotech,
`Cougar Biotechnology, Dendreon, Exelixis,
`GlaxoSmithKline, Medivation Millinium/Takeda, Lilly,
`Oncogenex, Pfizer, Sanofi‑Aventis, Serono, and Teva.
`See the article online for full details of the
`relationships.
`
`3.
`
`5.
`
`1. de Bono, J. S. et al. Abiraterone and increased
`survival in metastatic prostate cancer. N. Engl.
`J. Med. 364, 1995–2005 (2011).
`2. Huggins, C. & Hodges, C. V. Studies on
`prostatic cancer. I. The effect of castration, of
`estrogen and androgen injection, on serum
`phosphatases in metastatic carcinoma of the
`prostate. Cancer Res. 1, 293–297 (1941).
`The Leuprolide Study Group. Leuprolide versus
`diethylstilbestrol for metastatic prostate cancer.
`N. Engl. J. Med. 311, 1281–1286 (1984).
`4. Petrylak, D. P. et al. Docetaxel and estramustine
`compared with mitoxantrone and prednisone
`for advanced refractory prostate cancer.
`N. Engl. J. Med. 351, 1513–1520 (2004).
`Tannock, I. F. et al. Docetaxel plus prednisone
`or mitoxantrone plus prednisone for advanced
`prostate cancer. N. Engl. J. Med. 351,
`1502–1512 (2004).
`6. Kantoff, P. W. et al. Sipuleucel‑T immunotherapy
`for castration‑resistant prostate cancer. N. Engl.
`J. Med. 363, 411–422 (2010).
`7. de Bono, J. S. et al. Prednisone plus cabazitaxel
`or mitoxantrone for metastatic castration‑
`resistant prostate cancer progressing after
`docetaxel treatment: a randomised open‑label
`trial. Lancet 376, 1147–1154 (2010).
`8. Bayer Press Server. Alpharadin significantly
`improves overall survival in phase III Trial in
`patients with castration-resistant prostate
`cancer that has spread to the bone [online],
`http://www.press.bayer.com/baynews/
`baynews.nsf/id/Alpharadin‑Significantly‑
`Improves‑Overall‑Survival‑Phase‑III‑Trial‑
`Patients‑Castration‑Resistant (2011).
`Logothetis, C. et al. Effect of abiraterone
`acetate (AA) on pain control and skeletal‑
`related events (SRE) in patients (pts) with
`metastatic castration‑resistant prostate cancer
`(mCRPC) post docetaxel (D): Results from the
`COU‑AA‑301 phase III study. [abstract 4520].
`J. Clin. Oncol. 29 (2011).
`10. Scher, H. I. et al. Evaluation of circulating tumor
`cell (CTC) enumeration as an efficacy response
`biomarker of overall survival (OS) in metastatic
`castration‑resistant prostate cancer (mCRPC):
`Planned final analysis (FA) of COU‑AA‑301, a
`randomized double‑blind, placebo‑controlled
`phase III study of abiraterone acetate (AA) plus
`low‑dose prednisone (P) post docetaxel.
`[abstract LBA4517]. J. Clin. Oncol. 29 (2011).
`
`9.
`
`516 | SEPTEMBER 2011 | VOLUME 8
`
`© 2011 Macmillan Publishers Limited. All rights reserved
`
`www.nature.com/nrclinonc
`
`WCK1042
`Page 2
`
`

`
`
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`
`
`ll41ula4Y.4lrrc.Jnduc..l.5..44»2;1..1/:/..l.(1r
`
`Nature reviews. Clinical oncology.
`v. 8, no. 9 (Sept. 2011)
`General Collection
`W1 NA8118
`2011-09-21 09:33:14
`
`>>,»DD§)
`
`;, September 2011 volume 8 no. 9
`.nature
`)
`.com/reviews
`
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`
`QY
`
`1
`
`PROPERTY or THE
`
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`MEDICINE
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`WCK1042
`Page 3
`
`

`
`CONTENTS
`
`RESEARCH HIGHLIGHTS
`
`Revisiting family history
`
`Go on, leave me BRCA—|ess!
`
`Repopulating tumor cells—dying for caspase 3
`
`Retargeting imatinib
`
`Triggering a bad stimulation
`
`Finding the smoking gun in lung cancer
`
`N EWS & VIEWS
`
`mnrzmeo ‘riirzrmpiasz Using [3-blockers to inhibit breast cancer
`progression
`Desmond G. Powe and Frank Entschladen
`
`mrzcsrzo THERAPIES3 Improved outcomes for patients
`with metastatic melanoma
`
`Vernon K. Sondak and Lawrence E. F/aherty
`
`COlVl8lNATlON THERAPY! Abiraterone prolongs survival in metastatic
`prostate cancer
`Oliver Sartor
`
`PERSPECTIVES
`
`OPll“llONI The inverted pyramid of biomarker—driven trials
`Ignacio Garrido—Laguna, Manuel Hidalgo and Razelle Kurzrock
`
`Phase I trials have evolved from simple dose—finding studies to
`studies that provide therapeutic opportunities for patients where
`no standard therapy is available; however, various factors have
`hampered patient recruitment to phase I trials. The authors
`discuss how matching patients with specific genetic aberrations
`to specific therapies will improve drug attrition rates and enhance
`patient outcomes.
`
`NATURE REVIEWS | cLTNicAL oNcoLocv'
`
`iritiirre
`REVIEWS
`
`c0PYRlGHT© 2011 Nature Publishing Group.
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`
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`Oncology (ISSN 1759-4774 [print]; 1759-
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`Publishing Group. Please cite articles as
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`Clin. Oncol. vol, xxx-xxx (year) [doi:10.1038/
`nrciinoncxxxx].
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