CCR Perspectives in Drug Approval
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Author Manuscript Published OnlineFirst on October 18, 2013; DOI: 10.1158/1078-0432.CCR-13-1763 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. CCR Perspectives in Drug Approval Enzalutamide for Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer Who Have Previously Received Docetaxel: U.S. Food and Drug Administration Drug Approval Summary Yangmin M. Ning1, William Pierce1, V. Ellen Maher1, Stella Karuri2, Sheng-Hui Tang2, Haw-Jyh Chiu1, Todd Palmby1, Jeanne Fourie Zirkelbach3, Dhananjay Marathe3, Nitin Mehrotra3, Qi Liu3, Debasis Ghosh4, Christy L. Cottrell1, John Leighton1, Rajeshwari Sridhara2, Amna Ibrahim1, Robert Justice1, and Richard Pazdur1 Abstract This article summarizes the regulatory evaluation that led to the full approval of enzalutamide (XTANDI®, Medivation Inc.) by the U. S. Food and Drug Administration (FDA) on August 31, 2012, for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received docetaxel. This approval was based on the results of a randomized, placebo-controlled trial which randomly allocated 1199 patients with mCRPC who had received prior docetaxel to receive either enzalutamide 160 mg orally once daily (N=800) or placebo (N=399). All patients were required to continue androgen deprivation therapy. The primary endpoint was overall survival. At the pre-specified interim analysis, a statistically significant improvement in overall survival was demonstrated for the enzalutamide arm compared to the placebo arm [HR=0.63 (95% CI: 0.53, 0.75), p < 0.0001]. The median overall survival time was 18.4 and 13.6 months in the enzalutamide and placebo arms, respectively. The most common adverse reactions (≥10%) included asthenia or fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, and upper respiratory infection. Seizures occurred in 0.9% of patients on enzalutamide compared to no patients on the placebo arm. Overall, the FDA’s review and analyses of the submitted data confirmed that enzalutamide had a favorable benefit-risk profile in the study patient population, thus supporting its use for the approved indication. The recommended dose is 160 mg enzalutamide administered orally once daily. Enzalutamide represents the third product that FDA has approved in the same disease setting within a period of 2 years. Downloaded from clincancerres.aacrjournals.org on March 14, 2021. © 2013 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on October 18, 2013; DOI: 10.1158/1078-0432.CCR-13-1763 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 2 Authors' Affiliation: 1Office of Hematology and Oncology Products, Office of New Drugs; 2Office of Biostatistics; 3 Office of Clinical Pharmacology; 4Office of New Drug Quality Assessment; Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland Note: YM Ning and W Pierce reviewed the clinical efficacy and safety of enzalutamide in the NDA, respectively. Corresponding Author: Yang-Min Ning, M.D., Ph.D. Office of Hematology and Oncology Products, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Building 22, Room 2139, Silver Spring, MD 20993; E-mail: ningy@cder.fda.gov Downloaded from clincancerres.aacrjournals.org on March 14, 2021. © 2013 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on October 18, 2013; DOI: 10.1158/1078-0432.CCR-13-1763 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 3 Introduction Docetaxel in combination with prednisone was the first FDA-approved chemotherapy that improves survival in patients with metastatic castration-resistant prostate cancer (mCRPC). It received full approval in 2004 based on a 2.4 month improvement in median overall survival (OS) for docetaxel compared to mitoxantrone [HR=0.76 (95% CI: 0.62, 0.94), p
Author Manuscript Published OnlineFirst on October 18, 2013; DOI: 10.1158/1078-0432.CCR-13-1763 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 4 Enzalutamide is an androgen receptor inhibitor. Its clinical development was initiated by Medivation Inc. in 2007. A Phase 1-2 study of enzalutamide (formerly named MDV3100) at oral doses ranging from 30 to 600 mg daily demonstrated promising antitumor activity in 133 patients with mCRPC who were either chemotherapy-naïve or previously treated with docetaxel (9, 10). Although this study determined that the maximum tolerated dose of enzalutamide was 240 mg once daily, an additional evaluation of the dose-related activity and safety data, particularly of the 3 cases of seizure occurring at the doses greater than 240 mg, led to the choice of using enzalutamide 160 mg once daily for further clinical studies. To evaluate whether the antitumor activity of enzalutamide could be translated into a tangible clinical benefit, the applicant conducted a randomized, placebo-controlled trial (CRPC2) in patients with mCRPC previously treated with docetaxel (11, 12). Patients with conditions that could predispose to seizure were excluded from this randomized trial. The new drug application (NDA) for enzalutamide was submitted and received by the FDA on May 22, 2012. This NDA was designated for a 6-month priority review and was approved on August 31, 2012, three months after submission. This article summarizes key findings from FDA’s multidisciplinary review teams, with a focus on the clinical review findings that support the approved indication. For more details, see the reviews of enzalutamide at Drugs@FDA (13). Chemistry Enzalutamide has a chemical designation as 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5- dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide. Its molecular formula is C21H16F4N4O2S, with a molecular weight of 464.44. Enzalutamide is a white crystalline non-hygroscopic solid that is practically insoluble in water. The inactive ingredients of XTANDI include caprylocaproyl polyoxylglycerides, butylated hydroxyanisole, butylated hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin, purified water, titanium dioxide, and black iron oxide. Downloaded from clincancerres.aacrjournals.org on March 14, 2021. © 2013 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on October 18, 2013; DOI: 10.1158/1078-0432.CCR-13-1763 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 5 XTANDI is provided as liquid-filled soft gelatin capsules. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides. Nonclinical pharmacology and toxicology In vitro, enzalutamide inhibited androgen binding to androgen receptors, androgen-dependent androgen receptor nuclear translocation, androgen-dependent androgen receptor association with DNA, and decreased proliferation and induced cell death of prostate cancer cells. In vivo, enzalutamide decreased tumor volume in a mouse xenograft model of human prostate cancer. Major target organ systems of toxicity that were identified in repeat-dose toxicity studies with enzalutamide in rats and dogs were the reproductive organs and central nervous system. Consistent with the pharmacological activity of enzalutamide, major toxicity findings were noted in male reproductive organs. In a 26-week study in rats, decreased organ weights were correlated with atrophy of the prostate and seminal vesicles, which were observed at systemic exposures similar to the human exposure based on AUC. In 4- and 13-week studies in dogs, decreased organ weights were correlated with hypospermatogenesis and atrophy of the prostate and epididymides, which were observed at 0.3 times the human AUC. Convulsions were noted in repeat-dose studies in mice and dogs. A dose-dependent increase in convulsions was observed in mice at 0.6 times the human AUC, and a convulsion was observed in one dog at 3.3 times the human AUC. Other nonclinical findings of minimal severity and without significant clinical correlations were noted in the liver (hepatocellular hypertrophy), pituitary (hypertrophy and hyperplasia), and kidney (chronic progressive nephropathy) following repeat-dose administration of enzalutamide to rats. Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma tk gene mutation assay or the in vivo mouse bone marrow micronucleus assay. Carcinogenicity studies with enzalutamide were not conducted or required to support approval for use in the indicated patient population. Enzalutamide is not indicated for use in female patients. Reproductive and developmental toxicology studies with enzalutamide were not required to support approval for use in the indicated patient population. However, based on its mechanism of action and findings from repeat-dose Downloaded from clincancerres.aacrjournals.org on March 14, 2021. © 2013 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on October 18, 2013; DOI: 10.1158/1078-0432.CCR-13-1763 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 6 toxicity studies in rats and dogs, enzalutamide may impair male fertility. In addition, enzalutamide can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Enzalutamide was assigned pregnancy category X and is contraindicated for use in pregnant women. Clinical pharmacology Following oral administration of enzalutamide, the median time to reach maximum plasma enzalutamide concentrations is 1 hour (range 0.5 to 3 hours). The mean terminal half-life for enzalutamide is 5.8 days. Enzalutamide steady state is achieved by Day 28, and the accumulation ratio is 8.3 fold. At steady state, enzalutamide showed approximately dose proportional pharmacokinetics over the daily dose range of 30 to 360 mg. Enzalutamide is primarily eliminated by hepatic metabolism. Following oral administration of 14C-enzalutamide, 71% and 14% of radioactivity were recovered in urine and feces, respectively. The major metabolite of enzalutamide, N-desmethyl enzalutamide, has similar in vitro activity to enzalutamide. The mean terminal half-life for N-desmethyl enzalutamide is 7.8 days. Food does not alter the systemic exposure of enzalutamide or N-desmethyl enzalutamide, and enzalutamide can be administered with or without food. Co-medications can significantly affect the exposure to enzalutamide. Co-administration of gemfibrozil (a strong CYP2C8 inhibitor) increased the composite exposure of enzalutamide plus N- desmethyl enzalutamide by 2.2-fold. The concomitant use of strong CYP2C8 inhibitors should be avoided if possible. If patients must be co-administered a strong CYP2C8 inhibitor, reduce the enzalutamide dose to 80 mg once daily. The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated, and co-administration of enzalutamide with strong and moderate CYP2C8 inducers should be avoided if possible. Co-administration of itraconazole (a strong CYP3A4 inhibitor) increased the composite exposure of enzalutamide plus N-desmethyl enzalutamide by 1.3-fold. The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated, and co-administration of enzalutamide with strong or moderate CYP3A4 inducers should be avoided if possible. Downloaded from clincancerres.aacrjournals.org on March 14, 2021. © 2013 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on October 18, 2013; DOI: 10.1158/1078-0432.CCR-13-1763 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 7 Enzalutamide can significantly affect the exposure to other co-medications. In vivo, enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer. At steady state, enzalutamide reduced the plasma exposure to midazolam (a CYP3A4 substrate), warfarin (a CYP2C9 substrate) and omeprazole (a CYP2C19 substrate) by 86%, 56% and 70%, respectively. Therefore, concomitant use of enzalutamide with narrow therapeutic index drugs that are metabolized by CYP3A4, CYP2C9 or CYP2C19 should be avoided if possible. If co- administration with warfarin (a CYP2C9 substrate) is unavoidable, conduct additional INR monitoring. No exposure-response relationship for overall survival (OS) could be identified for enzalutamide within a single fixed dose of 160 mg/day in the phase 3 CRPC2 trial. An exposure-response analysis for seizure was not possible due to its low incidence in the trial; however, four patients who were reported to have a seizure and who had available pharmacokinetic data belonged to the higher exposure quartiles (Q3/Q4) rather than the lower exposure quartiles (Q1/Q2). The recommendation for dose adjustment when co-administered with strong CYP2C8 inhibitors is intended to keep the enzalutamide exposures within the concentration range that has been studied. No starting dose adjustment is needed for patients with creatinine clearance (CrCL) greater than 30 mL/min. Clinical and pharmacokinetic data are insufficient to assess the potential effect of severe renal impairment (CrCL < 30 mL/min) on enzalutamide pharmacokinetics. The composite exposure of enzalutamide and N-desmethyl enzalutamide following a single dose of enzalutamide was similar in subjects with baseline mild or moderate hepatic impairment (Child- Pugh Class A and B, respectively) versus those with normal hepatic function, and no starting dose adjustment is needed. Enzalutamide has not been studied in subjects with baseline severe hepatic impairment (Child-Pugh Class C). Clinical Studies Downloaded from clincancerres.aacrjournals.org on March 14, 2021. © 2013 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on October 18, 2013; DOI: 10.1158/1078-0432.CCR-13-1763 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 8 This NDA was primarily based on results from the CRPC2 trial and was supported by data from two open-label, single-arm Phase 1-2 studies in the same or similar patient populations. The clinical review found that the two open-label studies showed similar PSA response rates (approximately 50%) and safety signals. Study design The CRPC2 trial was a randomized, double-blind, placebo-controlled, multicenter Phase 3 trial comparing the efficacy and safety of once daily dosing of enzalutamide to that of placebo in patients with mCRPC who had previously received docetaxel. The primary endpoint was overall survival. Key secondary endpoints included radiographic progression-free survival, time to PSA progression, and the percentage of confirmed PSA declines of ≥50%. Patients had to have documented evidence of disease progression by PSA and/or radiographic scans while maintaining castrate levels of testosterone. Patients with the following conditions were excluded: prostate cancer with evidence of neuroendocrine differentiation or small cell features, or with evidence of metastases in the brain or active epidural disease; a history of seizure, including any febrile seizure, loss of consciousness, or transient ischemia attack within 12 months of enrollment, or any condition that may pre-dispose to seizure (e.g., prior stroke, brain arteriovenous malformation, head trauma with loss of consciousness requiring hospitalization); or taking medicines known to decrease the seizure threshold. Patients were randomly allocated 2:1 to receive either enzalutamide orally at a dose of 160 mg once daily or placebo orally once daily. All patients continued androgen deprivation therapy during the trial. Patients were allowed, but not required to continue or initiate systemic use of glucocorticoids. Study treatment continued until patients experienced disease progression (evidence of radiographic progression, a skeletal-related event, or clinical progression), initiation of new treatment for the disease, unacceptable toxicity, or withdrawal. Downloaded from clincancerres.aacrjournals.org on March 14, 2021. © 2013 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on October 18, 2013; DOI: 10.1158/1078-0432.CCR-13-1763 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 9 All randomized patients constituted the intent-to-treat (ITT) population, regardless of whether the actual allocated study treatment was administered or not. Primary efficacy analyses were conducted in the ITT population. In contrast, the safety population consisted of all patients who received at least one dose of study treatment. Patient baseline characteristics This trial enrolled 1199 patients from 156 study centers in 15 countries, with 800 patients allocated to the enzalutamide arm and 399 to the placebo arm. Twenty-four percent of the patients were recruited from the United States. Baseline demographics were balanced between the two arms. The median age was 69 years (range 41-92) and the distribution by race was 93% Caucasian, 4% Black, 1% Asian, and 2% Other. Key disease characteristics, as summarized in Table 1, were generally balanced between the two arms at study entry. Of note, 91% of patients had metastases in bone and 23% had visceral involvement in the lung and/or liver. The percentage of patients with visceral involvement was 4% more in the enzalutamide arm than that in the placebo arm, which may favor the placebo arm in terms of prognosis. All patients had received prior docetaxel-based chemotherapy and 24% of the patients had received two cytotoxic chemotherapy regimens. The prior docetaxel usage, including the cumulative dosage (Table 1) and the time intervals of docetaxel use relative to the initiation of study treatment appears balanced between the arms (13). Prior use of the marketed androgen receptor antagonists was examined and found to be balanced between the two arms. Across the arms, 85% of patients used bicalutamide, 14% used flutamide, and 10% used nilutamide. Efficacy results Downloaded from clincancerres.aacrjournals.org on March 14, 2021. © 2013 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on October 18, 2013; DOI: 10.1158/1078-0432.CCR-13-1763 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 10 Analysis of the primary endpoint OS was conducted according to the pre-specified interim analysis plan with a total of 520 events (80% of the events required for the planned final analysis). The analysis demonstrated a statistically significant improvement in OS in patients on the enzalutamide arm compared to patients on the placebo arm [stratified HR 0.63 (95% CI: 0.53, 0.75), p
Author Manuscript Published OnlineFirst on October 18, 2013; DOI: 10.1158/1078-0432.CCR-13-1763 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 11 Table 2 summarizes the adverse reactions occurring at a ≥ 2% absolute increase in frequency in the enzalutamide arm compared to the placebo arm. The most common adverse reactions with an incidence frequency of ≥10% included asthenia or fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, and upper respiratory infection. Other common adverse reactions (≥5% but
Author Manuscript Published OnlineFirst on October 18, 2013; DOI: 10.1158/1078-0432.CCR-13-1763 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 12 seizure were excluded from the randomized trial, it is important to assess whether patients with pre- disposing risk factors for seizure can safely tolerate this medication. The need for a trial to assess this risk was identified during the review. The trial will be conducted by the applicant as a post- marketing requirement. Based on similar PSA response rates with enzalutamide in patients who were chemotherapy-naïve and in patients who received prior docetaxel (10), a randomized, placebo-controlled Phase 3 trial is ongoing to investigate the effectiveness and safety of enzalutamide in chemotherapy-naïve patients with mCRPC (14). Results from this trial may help provide additional information about how to best use enzalutamide in the treatment of patients with mCRPC. The FDA’s approval of enzalutamide provides a new treatment option for patients with mCRPC who have received prior docetaxel. Enzalutamide is the third product approved for use in patients with mCRPC in the last 2 years (4, 5, 13). These three products, cabazitaxel, abiraterone acetate, and enzalutamide, differ in their mechanism of action and benefit-risk profile, and will provide more options in the treatment of patients with mCRPC. Nevertheless, choice of a treatment from the three products will need best assessments of patient’s overall disease condition relative to the known benefit-risk profile. Comparative effectiveness studies may help define what sequence or combination of the products is more beneficial to patients. Downloaded from clincancerres.aacrjournals.org on March 14, 2021. © 2013 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on October 18, 2013; DOI: 10.1158/1078-0432.CCR-13-1763 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 13 Disclosure of Potential Conflicts of Interest All the authors have no conflicts of interests to disclose. Authors' Contributions Downloaded from clincancerres.aacrjournals.org on March 14, 2021. © 2013 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on October 18, 2013; DOI: 10.1158/1078-0432.CCR-13-1763 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 14 References 1. Dagher R, Li N, Abraham S, Rahman A, Sridhara R, Pazdur R. Approval summary: Docetaxel in combination with prednisone for the treatment of androgen-independent hormone-refractory prostate cancer. Clin Cancer Res 2004;10:8147-51. 2. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502-12. 3. de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 2010;376:1147-54. 4. Cabazitaxel FDA Medical Review, 2010. (http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/201023s000MedR.pdf) 5. Abiraterone Acetate FDA Medical Review, 2011. (http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202379Orig1s000MedR.pdf) 6. Attard G, Reid AH, Yap TA, 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 commonly remains hormone driven. J Clin Oncol 2008;26:4563-71. 7. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN,et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995-2005. 8. Chen Y, Clegg NJ, Scher HI. Anti-androgens and androgen-depleting therapies in prostate cancer: new agents for an established target. Lancet Oncol. 2009;10:981-91. Downloaded from clincancerres.aacrjournals.org on March 14, 2021. © 2013 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on October 18, 2013; DOI: 10.1158/1078-0432.CCR-13-1763 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 15 9. Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324:787-90. 10. Scher HI, Beer TM, Higano CS, Anand A, Taplin ME, Efstathiou E, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet 2010;375:1437-46. 11. Medivation, Inc. A multinational Phase 3, randomized, double-blind, placebo-controlled efficacy and safety study of oral MDV3100 in patients with progressive castration- resistant prostate cancer previously treated with docetaxel-based chemotherapy. ClinicalTrials.gov Identifier: NCT00974311; first received on September 9, 2009. 12. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187- 97. 13. Enzalutamide FDA Multidisciplinary Reviews, 2012. (http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203415_xtandi_toc.cfm) 14. Medivation, Inc. A multinational Phase 3, randomized, double-blind, placebo-controlled efficacy and safety study of oral MDV3100 in chemotherapy-naive patients with progressive metastatic prostate cancer who have failed androgen deprivation therapy. ClinicalTrials.gov Identifier: NCT01212991; first received on September 29, 2010. Downloaded from clincancerres.aacrjournals.org on March 14, 2021. © 2013 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on October 18, 2013; DOI: 10.1158/1078-0432.CCR-13-1763 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 16 Figure Legend: Figure 1: Kaplan-Meier curves of overall survival from the CRPC2 trial. XTANDI is the proprietary name of enzalutamide. Hazard Ratio was derived from a stratified proportional hazards model. Adapted from the original XTANDI product label, © 2012 Astellas Pharma US, Inc. Downloaded from clincancerres.aacrjournals.org on March 14, 2021. © 2013 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on October 18, 2013; DOI: 10.1158/1078-0432.CCR-13-1763 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 17 Table 1: Key Baseline Disease Characteristics in the CRPC2 Trial Enzalutamide Placebo (N=800) (N=399) Disease Progression Type* PSA-only Progression 326 (41%) 164 (41%) Radiographic Progression 470 (59%) 234 (59%) Disease Metastasis Site Bone 730 (92%) 364 (92%) Lymph Node 442 (56%) 219 (55%) Viscera (Liver, Lung) 196 (25%) 82 (21%) Total Gleason Score at Diagnosis ≤7 359 (45%) 175 (44%) ≥8 366 (46%) 193 (48%) Missing 75 (9%) 31 (8%) Serum PSA Level (ng/mL) Median (range) 108 (0.4, 11794) 128 (0.6, 19000) ECOG Score 0 298 (37%) 156 (39%) 1 432 (54%) 211 (53%) 2 70 (9%) 32 (8%) BPI-SF Pain Score a (Mean) ≥4 225 (28%) 115 (29%) 0 429 (54%) 199 (50%) =0 146 (18%) 85 (21%) Prior Chemotherapy Use Number of Regimens (%) 1 72% 74% 2 25% 24% ≥3 b 3% 2% Total Docetaxel Usage c (mg) Median (range) 600 600 (25, 2520) (75, 2175) * Reported at the time of screening for this trial a: Baseline BPI-SF pain score of ≥4 (Average of patient’s reported scores over the 7 days prior to randomization). b: Representing a protocol deviation c: Reported in 86% patients. Prior docetaxel usage information was collected retrospectively. Downloaded from clincancerres.aacrjournals.org on March 14, 2021. © 2013 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on October 18, 2013; DOI: 10.1158/1078-0432.CCR-13-1763 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Table 2: Adverse Reactions in the CRPC2 Trial Enzalutamide Placebo (N=800) (N=399) Grade 1-4 (%) Grade 3-4(%) Grade 1-4 (%) Grade 3-4 (%) General Disorders Asthenic Conditionsa 50.6 9.0 44.4 9.3 Peripheral Edema 15.4 1.0 13.3 0.8 Musculoskeletal And Connective Tissue Disorders Back Pain 26.4 5.3 24.3 4.0 Arthralgia 20.5 2.5 17.3 1.8 Musculoskeletal Pain 15.0 1.3 11.5 0.3 Muscular Weakness 9.8 1.5 6.8 1.8 Musculoskeletal Stiffness 2.6 0.3 0.3 0.0 Gastrointestinal Disorders Diarrhea 21.8 1.1 17.5 0.3 Vascular Disorders Hot Flush 20.3 0.0 10.3 0.0 Hypertension 6.4 2.1 2.8 1.3 Nervous System Disorders Headache 12.1 0.9 5.5 0.0 Dizzinessb 9.5 0.5 7.5 0.5 Spinal Cord Compression and 7.4 6.6 4.5 3.8 Cauda Equina Syndrome Paresthesia 6.6 0.0 4.5 0.0 Mental Impairment Disordersc 4.3 0.3 1.8 0.0 Hypoesthesia 4.0 0.3 1.8 0.0 Infections And Infestations Upper Respiratory Tract 10.9 0.0 6.5 0.3 Infectiond Lower Respiratory Tract And 8.5 2.4 4.8 1.3 Lung Infectione Psychiatric Disorders Insomnia 8.8 0.0 6.0 0.5 Anxiety 6.5 0.3 4.0 0.0 Renal And Urinary Disorders Hematuria 6.9 1.8 4.5 1.0 Pollakiuria 4.8 0.0 2.5 0.0 Injury, Poisoning And Procedural Complications Fall 4.6 0.3 1.3 0.0 Non-pathologic Fractures 4.0 1.4 0.8 0.3 Skin And Subcutaneous Tissue Disorders Pruritus 3.8 0.0 1.3 0.0 Dry Skin 3.5 0.0 1.3 0.0 Respiratory Disorders Epistaxis 3.3 0.1 1.3 0.3 a Includes asthenia and fatigue. Discontinuations due to fatigue were reported for 0.6% of enzalutamide-treated patients and 0.5% of placebo-treated patients. b Includes dizziness and vertigo. c Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. d Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. e Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection. Note: all adverse reactions were graded using the NCI Common Terminology Criteria for Adverse Events version 4 Downloaded from clincancerres.aacrjournals.org on March 14, 2021. © 2013 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on October 18, 2013; DOI: 10.1158/1078-0432.CCR-13-1763 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Figure 1: 100% 80% 60% Survival (%) 40% XTANDI (n = 800) Median 18.4 months Placebo (N = 399) Median 13.6 months 20% Hazard ratio = 0.63 95% CI (0.53, 0.75) P < 0.0001 0% 0 3 6 9 12 15 18 21 24 Months XTANDI 800 775 701 627 400 211 72 7 0 Placebo 399 376 317 263 167 81 33 3 0 Downloaded from clincancerres.aacrjournals.org on March 14, 2021. © 2013 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on October 18, 2013; DOI: 10.1158/1078-0432.CCR-13-1763 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Enzalutamide for Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer Who Have Previously Received Docetaxel: U.S. Food and Drug Administration Drug Approval Summary Yangmin M Ning, William Pierce, V Ellen Maher, et al. Clin Cancer Res Published OnlineFirst October 18, 2013. Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-13-1763 Author Author manuscripts have been peer reviewed and accepted for publication but have not yet been Manuscript edited. E-mail alerts Sign up to receive free email-alerts related to this article or journal. Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Subscriptions Department at pubs@aacr.org. Permissions To request permission to re-use all or part of this article, use this link http://clincancerres.aacrjournals.org/content/early/2013/10/18/1078-0432.CCR-13-1763. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site. Downloaded from clincancerres.aacrjournals.org on March 14, 2021. © 2013 American Association for Cancer Research.
You can also read