Challenges to improved therapeutics for metastatic castrate resistant prostate cancer: from recent successes and failures

Xuan Huang, Cindy H Chau, William D Figg, Xuan Huang, Cindy H Chau, William D Figg

Abstract

Men with metastatic castration-resistant prostate cancer (mCRPC) carry poor prognosis despite the use of docetaxel-based regimens which has modest survival benefit shown by randomized clinical trials. Significant progress in the discovery of novel therapeutic agents has been made in the past few years. While sipuleucel-T, cabazitaxel, and abiraterone gained regulatory approval in 2010 and 2011, several highly promising candidates/regimens have failed in large scale clinical trials. Challenges remain to optimize the design and interpretation of clinical trial results and develop more effective strategies for mCRPC. In this review, we examined the positive and negative clinical trials in mCRPC in the past and discussed the various aspects of clinical trial design including selection of targets and appropriate outcome measures, biomarker development and implementation, and strategies for combination therapy.

Trial registration: ClinicalTrials.gov NCT00104715 NCT00268476 NCT01400555 NCT01511536.

References

    1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10–29. doi: 10.3322/caac.20138.
    1. Petrylak DP, Tangen CM, Hussain MH, Lara PN, Jones JA, Taplin ME, Burch PA, Berry D, Moinpour C, Kohli M, Benson MC, Small EJ, Raghavan D, Crawford ED. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351:1513–1520. doi: 10.1056/NEJMoa041318.
    1. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Theodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA. TAX 327 Investigators: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502–1512. doi: 10.1056/NEJMoa040720.
    1. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, Xu Y, Frohlich MW, Schellhammer PF. IMPACT Study Investigators: Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411–422. doi: 10.1056/NEJMoa1001294.
    1. de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, Gravis G, Bodrogi I, Mackenzie MJ, Shen L, Roessner M, Gupta S, Sartor AO. TROPIC Investigators: Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376:1147–1154. doi: 10.1016/S0140-6736(10)61389-X.
    1. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN, Ellard SL, Fléchon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T. et al.Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995–2005. doi: 10.1056/NEJMoa1014618.
    1. Kris MG, Benowitz SI, Adams S, Diller L, Ganz P, Kahlenberg MS, Le QT, Markman M, Masters GA, Newman L, Obel JC, Seidman AD, Smith SM, Vogelzang N, Petrelli NJ. Clinical cancer advances 2010: annual report on progress against cancer from the american society of clinical oncology. J Clin Oncol. 2010;28:5327–5347. doi: 10.1200/JCO.2010.33.2742.
    1. Sartor AO. Progression of metastatic castrate-resistant prostate cancer: impact of therapeutic intervention in the post-docetaxel space. J Hematol Oncol. 2011;4:18. doi: 10.1186/1756-8722-4-18.
    1. Antonarakis ES, Carducci MA, Eisenberger MA. Novel targeted therapeutics for metastatic castration-resistant prostate cancer. Cancer Lett. 2010;291:1–13. doi: 10.1016/j.canlet.2009.08.012.
    1. Galsky MD, Vogelzang NJ. Docetaxel-based combination therapy for castration-resistant prostate cancer. Ann Oncol. 2010;21:2135–2144. doi: 10.1093/annonc/mdq050.
    1. Fizazi K, Carducci M, Smith M, Damiao R, Brown J, Karsh L, Milecki P, Shore N, Rader M, Wang H, Jiang Q, Tadros S, Dansey R, Goessl C. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377:813–822. doi: 10.1016/S0140-6736(10)62344-6.
    1. Sartor AO HD, Helle SI, O'Sullivan JM, Fossa SD, Chodacki A, Demkow T, Logue JP, Seke M, Widmark A, Johannessen DC, Nilsson S, Hoskin P, Solberg A, James ND, Syndikus I, Vogelzang NJ, O'Bryan-Tear CG, Shan M, Parker C. Radium-223 chloride impact on skeletal-related events in patients with castration-resistant prostate cancer (CRPC) with bone metastases: A phase III randomized trial (ALSYMPCA) J Clin Oncol. 2012;30(abstr 9)
    1. Scher HI, Sawyers CL. Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol. 2005;23:8253–8261. doi: 10.1200/JCO.2005.03.4777.
    1. Scher HI, Beer TM, Higano CS, Anand A, Taplin ME, Efstathiou E, Rathkopf D, Shelkey J, Yu EY, Alumkal J, Hung D, Hirmand M, Seely L, Morris MJ, Danila DC, Humm J, Larson S, Fleisher M, Sawyers CL. Prostate Cancer Foundation/Department of Defense Prostate Cancer Clinical Trials Consortium: Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study. Lancet. 2010;375:1437–1446. doi: 10.1016/S0140-6736(10)60172-9.
    1. Scher HI FK, Saad F, Taplin M, Sternberg CN, Miller K, De Wit R, Mulders P, Hirmand M, Selby B, De Bono JS. AFFIRM Investigators. Effect of MDV3100, an androgen receptor signaling inhibitor (ARSI), on overall survival in patients with prostate cancer postdocetaxel: Results from the phase III AFFIRM study. J Clin Oncol. 2012;30(5) LBA1.
    1. Wu-Wong JR, Chiou WJ, Wang J. Extracellular signal-regulated kinases are involved in the antiapoptotic effect of endothelin-1. J Pharmacol Exp Ther. 2000;293:514–521.
    1. Carducci MA, Jimeno A. Targeting bone metastasis in prostate cancer with endothelin receptor antagonists. Clin Cancer Res. 2006;12:6296s–6300s. doi: 10.1158/1078-0432.CCR-06-0929.
    1. James ND, Caty A, Borre M, Zonnenberg BA, Beuzeboc P, Morris T, Phung D, Dawson NA. Safety and efficacy of the specific endothelin-A receptor antagonist ZD4054 in patients with hormone-resistant prostate cancer and bone metastases who were pain free or mildly symptomatic: a double-blind, placebo-controlled, randomised, phase 2 trial. Eur Urol. 2009;55:1112–1123. doi: 10.1016/j.eururo.2008.11.002.
    1. James ND, Caty A, Payne H, Borre M, Zonnenberg BA, Beuzeboc P, McIntosh S, Morris T, Phung D, Dawson NA. Final safety and efficacy analysis of the specific endothelin A receptor antagonist zibotentan (ZD4054) in patients with metastatic castration-resistant prostate cancer and bone metastases who were pain-free or mildly symptomatic for pain: a double-blind, placebo-controlled, randomized Phase II trial. BJU Int. 2010;106:966–973. doi: 10.1111/j.1464-410X.2010.09638.x.
    1. Fizazi K, Miller K. Specific endothelin-A receptor antagonism for the treatment of advanced prostate cancer. BJU Int. 2009;104:1423–1425. doi: 10.1111/j.1464-410X.2009.08740.x.
    1. Nelson JB, Fizazi K, Miller K, Higano CS, Moul JW, Morris T, McIntosh S, Pemberton K, Gleave ME. Phase III study of the efficacy and safety of zibotentan (ZD4054) in patients with bone metastatic castration-resistant prostate cancer (CRPC) J Clin Oncol. 2011;29(abstr 117)
    1. Michaelson MD, Oudard S, Ou Y, Sengeløv L, Saad F, Houede N, Ostler PJ, Stenzl A, Daugaard G, Jones RJ, Laestadius F, Bahl A, Castellano DE, Gschwend J, Maurina T, Ye D, Chen I, Wang S, Maneval EC. Randomized, placebo-controlled, phase III trial of sunitinib in combination with prednisone (SU+P) versus prednisone (P) alone in men with progressive metastatic castration-resistant prostate cancer (mCRPC) J Clin Oncol. 2011;29(abstr 4515)
    1. Dror Michaelson M, Regan MM, Oh WK, Kaufman DS, Olivier K, Michaelson SZ, Spicer B, Gurski C, Kantoff PW, Smith MR. Phase II study of sunitinib in men with advanced prostate cancer. Ann Oncol. 2009;20:913–920. doi: 10.1093/annonc/mdp111.
    1. Sonpavde G, Periman PO, Bernold D, Weckstein D, Fleming MT, Galsky MD, Berry WR, Zhan F, Boehm KA, Asmar L, Hutson TE. Sunitinib malate for metastatic castration-resistant prostate cancer following docetaxel-based chemotherapy. Ann Oncol. 2010;21:319–324. doi: 10.1093/annonc/mdp323.
    1. Dahut WL, Scripture C, Posadas E, Jain L, Gulley JL, Arlen PM, Wright JJ, Yu Y, Cao L, Steinberg SM, Aragon-Ching JB, Venitz J, Jones E, Chen CC, Figg WD. A phase II clinical trial of sorafenib in androgen-independent prostate cancer. Clin Cancer Res. 2008;14:209–214. doi: 10.1158/1078-0432.CCR-07-1355.
    1. Kelly WK, Scher HI, Mazumdar M, Vlamis V, Schwartz M, Fossa SD. Prostate-specific antigen as a measure of disease outcome in metastatic hormone-refractory prostate cancer. J Clin Oncol. 1993;11:607–615.
    1. Bubley GJ, Carducci M, Dahut W, Dawson N, Daliani D, Eisenberger M, Figg WD, Freidlin B, Halabi S, Hudes G, Hussain M, Kaplan R, Myers C, Oh W, Petrylak DP, Reed E, Roth B, Sartor O, Scher H, Simons J, Sinibaldi V, Small EJ, Smith MR, Trump DL, Vollmer R, Wilding G. Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol. 1999;17:3461–3467.
    1. Petrylak DP, Ankerst DP, Jiang CS, Tangen CM, Hussain MH, Lara PN, Jones JA, Taplin ME, Burch PA, Kohli M, Benson MC, Small EJ, Raghavan D, Crawford ED. Evaluation of prostate-specific antigen declines for surrogacy in patients treated on SWOG 99–16. J Natl Cancer Inst. 2006;98:516–521. doi: 10.1093/jnci/djj129.
    1. Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger MA, Higano C, Bubley GJ, Dreicer R, Petrylak D, Kantoff P, Basch E, Kelly WK, Figg WD, Small EJ, Beer TM, Wilding G, Martin A, Hussain M. Prostate Cancer Clinical Trials Working Group: Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008;26:1148–1159. doi: 10.1200/JCO.2007.12.4487.
    1. Dixon SC, Knopf KB, Figg WD. The control of prostate-specific antigen expression and gene regulation by pharmacological agents. Pharmacol Rev. 2001;53:73–91.
    1. Fleming MT, Morris MJ, Heller G, Scher HI. Post-therapy changes in PSA as an outcome measure in prostate cancer clinical trials. Nat Clin Pract Oncol. 2006;3:658–667.
    1. Meirelles GS, Schoder H, Ravizzini GC, Gonen M, Fox JJ, Humm J, Morris MJ, Scher HI, Larson SM. Prognostic Value of Baseline [18 F] Fluorodeoxyglucose Positron Emission Tomography and 99mTc-MDP Bone Scan in Progressing Metastatic Prostate Cancer. Clin Cancer Res. 2010;16:6093–6099. doi: 10.1158/1078-0432.CCR-10-1357.
    1. Scher HI, Morris MJ, Kelly WK, Schwartz LH, Heller G. Prostate cancer clinical trial end points: "RECIST"ing a step backwards. Clin Cancer Res. 2005;11:5223–5232. doi: 10.1158/1078-0432.CCR-05-0109.
    1. Aragon-Ching JB, Jain L, Gulley JL, Arlen PM, Wright JJ, Steinberg SM, Draper D, Venitz J, Jones E, Chen CC, Figg WD, Dahut WL. Final analysis of a phase II trial using sorafenib for metastatic castration-resistant prostate cancer. BJU Int. 2009;103:1636–1640. doi: 10.1111/j.1464-410X.2008.08327.x.
    1. Halabi S, Vogelzang NJ, Ou SS, Owzar K, Archer L, Small EJ. Progression-free survival as a predictor of overall survival in men with castrate-resistant prostate cancer. J Clin Oncol. 2009;27:2766–2771. doi: 10.1200/JCO.2008.18.9159.
    1. Scher HI, Warren M, Heller G. The association between measures of progression and survival in castrate-metastatic prostate cancer. Clin Cancer Res. 2007;13:1488–1492. doi: 10.1158/1078-0432.CCR-06-1885.
    1. Kelly WK, Halabi S, Carducci M, George D, Mahoney JF, Stadler WM, Morris M, Kantoff P, Monk JP, Kaplan E, Vogelzang NJ, Small EJ. Randomized, Double-Blind, Placebo-Controlled Phase III Trial Comparing Docetaxel and Prednisone With or Without Bevacizumab in Men With Metastatic Castration-Resistant Prostate Cancer: CALGB 90401. J Clin Oncol. 2012;30(13):1534–1540. doi: 10.1200/JCO.2011.39.4767.
    1. Picus J, Halabi S, Kelly WK, Vogelzang NJ, Whang YE, Kaplan EB, Stadler WM, Small EJ. A phase 2 study of estramustine, docetaxel, and bevacizumab in men with castrate-resistant prostate cancer: results from Cancer and Leukemia Group B Study 90006. Cancer. 2011;117(3):526–533. doi: 10.1002/cncr.25421.
    1. Sternberg CN, Petrylak DP, Sartor O, Witjes JA, Demkow T, Ferrero JM, Eymard JC, Falcon S, Calabro F, James N, Bodrogi I, Harper P, Wirth M, Berry W, Petrone ME, McKearn TJ, Noursalehi M, George M, Rozencweig M. Multinational, double-blind, phase III study of prednisone and either satraplatin or placebo in patients with castrate-refractory prostate cancer progressing after prior chemotherapy: the SPARC trial. J Clin Oncol. 2009;27:5431–5438. doi: 10.1200/JCO.2008.20.1228.
    1. Buyse M. Use of meta-analysis for the validation of surrogate endpoints and biomarkers in cancer trials. Cancer J. 2009;15:421–425. doi: 10.1097/PPO.0b013e3181b9c602.
    1. Sutcliffe P, Hummel S, Simpson E, Young T, Rees A, Wilkinson A, Hamdy F, Clarke N, Staffurth J. Use of classical and novel biomarkers as prognostic risk factors for localised prostate cancer: a systematic review. Health Technol Assess. 2009;13(iii, xi-xiii):1–219.
    1. Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, Varambally S, Cao X, Tchinda J, Kuefer R, Lee C, Montie JE, Shah RB, Pienta KJ, Rubin MA, Chinnaiyan AM. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science. 2005;310:644–648. doi: 10.1126/science.1117679.
    1. Attard G, Swennenhuis JF, Olmos D, Reid AH, Vickers E, A'Hern R, Levink R, Coumans F, Moreira J, Riisnaes R, Oommen NB, Hawche G, Jameson C, Thompson E, Sipkema R, Carden CP, Parker C, Dearnaley D, Kaye SB, Cooper CS, Molina A, Cox ME, Terstappen LW, de Bono JS. Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer. Cancer Res. 2009;69:2912–2918. doi: 10.1158/0008-5472.CAN-08-3667.
    1. Tomlins SA, Bjartell A, Chinnaiyan AM, Jenster G, Nam RK, Rubin MA, Schalken JA. ETS gene fusions in prostate cancer: from discovery to daily clinical practice. Eur Urol. 2009;56:275–286. doi: 10.1016/j.eururo.2009.04.036.
    1. Sun C, Dobi A, Mohamed A, Li H, Thangapazham RL, Furusato B, Shaheduzzaman S, Tan SH, Vaidyanathan G, Whitman E, Hawksworth DJ, Chen Y, Nau M, Patel V, Vahey M, Gutkind JS, Sreenath T, Petrovics G, Sesterhenn IA, McLeod DG, Srivastava S. TMPRSS2-ERG fusion, a common genomic alteration in prostate cancer activates C-MYC and abrogates prostate epithelial differentiation. Oncogene. 2008;27:5348–5353. doi: 10.1038/onc.2008.183.
    1. Sharifi N, Dahut WL, Figg WD. The genetics of castration-resistant prostate cancer: what can the germline tell us? Clin Cancer Res. 2008;14:4691–4693. doi: 10.1158/1078-0432.CCR-08-0453.
    1. Jadvar H. Prostate Cancer: PET with 18 F-FDG, 18 F- or 11 C-Acetate, and 18 F- or 11 C-Choline. J Nucl Med. 2011;52:81–89. doi: 10.2967/jnumed.110.077941.
    1. Karakunnel JJ GJ, Arlen PM, Mulquin M, Wright JJ, Turkbey IB, Choyke P, Ahlers CM, Figg WD, Dahut WL. Phase II trial of cediranib (AZD2171) in docetaxel-resistant, castrate-resistant prostate cancer (CRPC) J Clin Oncol. 2008;26(abstr 5136)
    1. Scher HI, Jia X, de Bono JS, Fleisher M, Pienta KJ, Raghavan D, Heller G. Circulating tumour cells as prognostic markers in progressive, castration-resistant prostate cancer: a reanalysis of IMMC38 trial data. Lancet Oncol. 2009;10:233–239. doi: 10.1016/S1470-2045(08)70340-1.
    1. de Bono JS, Scher HI, Montgomery RB, Parker C, Miller MC, Tissing H, Doyle GV, Terstappen LW, Pienta KJ, Raghavan D. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2008;14:6302–6309. doi: 10.1158/1078-0432.CCR-08-0872.
    1. Attard G, Reid AH, A'Hern R, Parker C, Oommen NB, Folkerd E, Messiou C, Molife LR, Maier G, Thompson E, Olmos D, Sinha R, Lee G, Dowsett M, Kaye SB, Dearnaley D, Kheoh T, Molina A, de Bono JS. Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin Oncol. 2009;27:3742–3748. doi: 10.1200/JCO.2008.20.0642.
    1. Reid AH, Attard G, Danila DC, Oommen NB, Olmos D, Fong PC, Molife LR, Hunt J, Messiou C, Parker C, Dearnaley D, Swennenhuis JF, Terstappen LW, Lee G, Kheoh T, Molina A, Ryan CJ, Small E, Scher HI, de Bono JS. Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. J Clin Oncol. 2010;28:1489–1495. doi: 10.1200/JCO.2009.24.6819.
    1. Danila DC, Morris MJ, de Bono JS, Ryan CJ, Denmeade SR, Smith MR, Taplin ME, Bubley GJ, Kheoh T, Haqq C, Molina A, Anand A, Koscuiszka M, Larson SM, Schwartz LH, Fleisher M, Scher HI. Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer. J Clin Oncol. 2010;28:1496–1501. doi: 10.1200/JCO.2009.25.9259.
    1. Zurita AJ, George DJ, Shore ND, Liu G, Wilding G, Hutson TE, Kozloff M, Mathew P, Harmon CS, Wang SL, Chen I, Maneval EC, Logothetis CJ. Sunitinib in combination with docetaxel and prednisone in chemotherapy-naive patients with metastatic, castration-resistant prostate cancer: a phase 1/2 clinical trial. Ann Oncol. 2011;23(3):688–694.
    1. Kelly WK HS, Carducci MA George D, Mahoney JF, Stadler WM, Morris M, Kantoff P, Monk JP, Kaplan E, Vogelzang NJ, Small EJ. A randomized, double-blind, placebo-controlled phase III trial comparing docetaxel, prednisone, and placebo with docetaxel, prednisone, and bevacizumab in men with metastatic castration-resistant prostate cancer (mCRPC): Survival results of CALGB 90401. J Clin Oncol. 2010;28(LBA4511)
    1. , ; [http://ircelgenecom/phoenixzhtml?c=111960&p=irol-newsArticle&ID=1633148&highlight>=]
    1. Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer. 2008;8:592–603. doi: 10.1038/nrc2442.
    1. Ning YM, Gulley JL, Arlen PM, Woo S, Steinberg SM, Wright JJ, Parnes HL, Trepel JB, Lee MJ, Kim YS, Sun H, Madan RA, Latham L, Jones E, Chen CC, Figg WD, Dahut WL. Phase II trial of bevacizumab, thalidomide, docetaxel, and prednisone in patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2010;28:2070–2076. doi: 10.1200/JCO.2009.25.4524.
    1. Figg WD, Woo S, Zhu W, Chen X, Ajiboye AS, Steinberg SM, Price DK, Wright JJ, Parnes HL, Arlen PM, Gulley JL, Dahut WL. A phase I clinical study of high dose ketoconazole plus weekly docetaxel for metastatic castration resistant prostate cancer. J Urol. 2010;183:2219–2226. doi: 10.1016/j.juro.2010.02.020.
    1. Small EJ, Halabi S, Dawson NA, Stadler WM, Rini BI, Picus J, Gable P, Torti FM, Kaplan E, Vogelzang NJ. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583) J Clin Oncol. 2004;22:1025–1033. doi: 10.1200/JCO.2004.06.037.
    1. Attard G, Reid AH, Yap TA, Raynaud F, Dowsett M, Settatree S, Barrett M, Parker C, Martins V, Folkerd E, Clark J, Cooper CS, Kaye SB, Dearnaley D, Lee G, de Bono JS. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol. 2008;26:4563–4571. doi: 10.1200/JCO.2007.15.9749.
    1. Sarker D, Workman P. Pharmacodynamic biomarkers for molecular cancer therapeutics. Adv Cancer Res. 2007;96:213–268.
    1. Tan DS, Thomas GV, Garrett MD, Banerji U, de Bono JS, Kaye SB, Workman P. Biomarker-driven early clinical trials in oncology: a paradigm shift in drug development. Cancer J. 2009;15:406–420. doi: 10.1097/PPO.0b013e3181bd0445.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner