2014/10/04 攝護 癌藥物 展的新趨勢 台大醫院腫瘤醫學部蔡育傑醫師
攝護 癌在台灣的現況 (2010) New cases Death No. 4,392 1,021 Median Age 74 80 Standardized ratio (per 100,000 population ) 28.77 6.04 For those with stage registration Stage I Stage II Stage III Stage IV Total 338 1377 594 1243 3552 9.5% 38.8% 16.7% 35.0% 100% 資料來源 : 99 年台灣癌症 記報告
攝護 癌的治療 早期 - 密切追蹤 - 手術 ( 傳統 / 腔鏡 / 機械手臂 ) - 放射治療 復 或晚期 ( 包含轉移 ) - 會先考慮賀爾蒙治療 - 去勢療法出現抗性的攝護 癌
男性賀爾蒙的作用 下視丘 腦下垂體 睪丸腎上 ( 次要 ) 攝護 Nat Rev Cancer 2002
減少血液中雄性素 賀爾蒙治療的策略 - 睪丸切除 - 作用在下視丘的藥物減少對睪丸的刺激 ( 打針 : Leuplin, Diphereline, Zoradex) 阻止雄性素與雄性素受體結合 - 口服男性賀爾蒙抑制劑 : Casodex, Fugerel, Androcur
減少血液中雄性素的方法 Nat Rev Clin Oncol. 2014;11:365-76
1966 年諾貝爾醫學獎得主 for his discoveries concerning hormonal treatment of prostatic cancer ( 因為他在攝護 癌賀爾蒙治療的 現..) Charles Brenton Huggins
睪丸切除 根除性睪丸切除術乃針對睪丸癌的患者 單純性睪丸切除術則是針對攝護 癌的病患, 要達到荷爾蒙治療的目的 - 不方便出門打針的患者 - 使用注射劑仍無法達到療效的病人 睪丸切除手術可能 生之併 症 : - 傷口血腫 (<1 登 ) - 傷口感染, 疼痛 (<1 登 ) - 陰囊水腫 (<1 登 ) - 其他因內科疾病 老年或麻醉等原因引起之併 症
作用在下視丘的藥物
以柳菩林為例 作用 : 抑制腦下垂體功能及睪丸激素分泌 作用, 來造成血清中男性荷爾蒙降低至去勢濃度, 因此可改善症狀, 並使腫瘤消退 治療 : 每個月注射一次 ( 有的醫院為三個月一次的劑型 ) 禁忌 : 對 GnRH-a 過敏者
注意事項 治療的初期, 體内睪固酮的分泌會有短暫的增加, 比較原有的症狀會有輕微的惡化現象, 但此種情況通常只維持數天 在治療期間, 因為睪固酮的下降, 會引起下列症狀出現 例如 : 熱潮紅 性慾降低 腸胃不適等現象, 但不嚴重 在治療時, 應該按月準時接受注射, 即每間隔 28 天注射一次
攝護 癌用賀爾蒙治療的歷史 1941: Huggins and Hodges first treated men with PCa with either orchiectomy or estrogen -> Changes in prostate size and observed that improvements in acid and alkaline phosphatases were associated with cancer-related symptom relief -> Many patients continued to have measurable levels of serum acid phosphatase, following medical or surgical castration
攝護 癌病人賀爾蒙治療的預後 EAU Guideline 2013
HRPC versus CRPC Hormone-refractory prostate cancer ( 賀爾蒙無效的攝護 癌,HRPC): Prostate cancer that is no longer helped by any form of hormone therapy. Castrate-resistant prostate cancer ( 去勢療法出現抗性的攝護 癌,CRPC): Prostate cancer that is still growing despite the fact that hormone therapy (orchiectomy/ LHRH agonist/ LHRH antagonist) is keeping the testosterone in the body at very low, castrate levels. -> 對傳統的賀爾蒙治療無效, 但對新型賀爾蒙可能有效 American Cancer Society
去勢療法出現抗性的攝護 癌 (CRPC) 歐洲泌尿醫學會 (EAU) 在 2014 年的定義 Castrate seam levels of testosterone (testosterone < 50 ng/dl or < 1.7 nmol/l) ( 血清中男性賀爾蒙的濃度已經達到閹割值 ) + Biochemical progression (3 consecutive rises of PSA, 1 week apart, resulting in two 50% increases over the nadir, with PSA > 2 ng/ml) or Radiological progression (The appearance of two or more bone lesions on bone scan or enlargement of a soft tissue lesion using RECIST)
( 桃紅色 : 還對去勢療法有效 ) 轉移性攝護 癌, 去勢療法有效 ( 土色 : 去勢療法出現抗性 ) 轉移性攝護 癌, 去勢療法無效 Prostate Cancer Disease Stages<br /> 攝護 局部 局部治療後 PSA 上升 Presented By Cora Sternberg at 2014 ASCO Annual Meeting
( 桃紅色 : 還對去勢療法有效 ) ( 土色 : 去勢療法出現抗性 ) 轉移性攝護 癌, 去勢療法有效 Prostate Cancer Disease Stages<br /> 攝護 局部 局部治療後 PSA 上升 去勢療法無效的非轉移性攝護 癌 去勢療法無效的轉移性攝護 癌 (mcrpc) Presented By Cora Sternberg at 2014 ASCO Annual Meeting
Denosumab Alpharadin Zoledronic acid Docetaxel Cabazitaxel Sipuleucel-T Enzalutamide Abiraterone 2002 2004 2010 2011 2012 2013
NEJM papers Jan. 1 2013; 368:138-148 19
Molecular States Framework for AR Activation in Prostate Cancer Hormone-sensitive PC Hormone-refractory PC Castrate-resistant PC J Clin Oncol. 2012;30: 644 6
攝護 癌用賀爾蒙治療的歷史 1941: Huggins and Hodges first treated men with PCa with either orchiectomy or estrogen -> Changes in prostate size and observed that improvements in acid and alkaline phosphatases were associated with cancer-related symptom relief -> Many patients continued to have measurable levels of serum acid phosphatase, following medical or surgical castration -> They considered this a clear indication that androgen production by the adrenal glands was ongoing
正常情況下雄性素分泌的比例 性腺功能正常的男性 大約 10% 的雄性素才是由腎上腺所分泌 腎上腺 攝護腺腫瘤 大部分雄性素於睪丸內合成 ( 約 90%) 睪丸 Ref: Zytiga monograph
去勢男性雄性素分泌的情形 腎上腺 去勢男性去勢之後, 腎上腺是雄性素的主要來源 攝護腺腫瘤細胞會將腎上腺的雄性素前驅物 (DHEA 和 androstenedione) 轉變成睪固酮和 DHT, 並產生內源性的雄性素, 以刺激其生長 攝護腺腫瘤 大部分雄性素於睪丸內合成 ( 約 90%) 睪丸 Ref: Zytiga monograph
(Abiraterone: 抑制腎上腺及癌細胞內雄性素分泌 ) Abiraterone inhibits CYP17:<br />17α-hydroxylase/17,20-lyase Presented By Cora Sternberg at 2014 ASCO Annual Meeting
抑制雄性素受體的方法 mcrpc Nat Rev Clin Oncol. 2014;11:365-76
(Enzalutamide/MDV3100: 阻斷雄性素受體功能 ) <br />Enzalutamide an AR signalling inhibitor: targets multiple steps in the (AR) signaling pathway<br /> Presented By Cora Sternberg at 2014 ASCO Annual Meeting
賀爾蒙治療的策略 ( 更新版 ) 減少血液中雄性素 - 睪丸切除 - 作用在下視丘的藥物減少對睪丸的刺激 ( 打針 : Leuplin, Diphereline, Zoradex) - 抑制腎上 分泌雄性素 ( 二側腎上 切除, ketoconazole, abiraterone) 阻止雄性素與雄性素受體結合 - 口服男性賀爾蒙抑制劑 : Casodex, Fugerel, Androcur - 新型賀爾蒙 : enzalutamide
<br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br />Abiraterone and Enzalutamide in mcrpc<br />Phase III Studies Post-docetaxel<br />(Primary Endpoint: OS)<br /> Presented By Cora Sternberg at 2014 ASCO Annual Meeting
COU-AA-301 Overall Survival <br />Median Benefit 4.6 Months Presented By Cora Sternberg at 2014 ASCO Annual Meeting
AFFIRM Overall Survival:<br />Median Benefit 4.8 Months Presented By Cora Sternberg at 2014 ASCO Annual Meeting
<br />Abiraterone and Enzalutamide in mcrpc<br />Phase III Studies Pre-docetaxel<br />(Primary Endpoint: rpfs and OS)<br /> Presented By Cora Sternberg at 2014 ASCO Annual Meeting
COU-AA-302: Interim Analysis Results of rpfs Presented By Cora Sternberg at 2014 ASCO Annual Meeting
Enzalutamide Prolonged Radiographic <br />Progression-Free Survival Presented By Cora Sternberg at 2014 ASCO Annual Meeting
Enzalutamide Reduced Risk of Death by 29% Presented By Cora Sternberg at 2014 ASCO Annual Meeting
mcrpc: NCCN Guideline
美國泌尿學會治療指引 J Urol. 2013 Aug;190(2):429-38 沒有轉移 有轉移 沒有接受過化療 有接受過化療
Index Patient 3: Symptomatic mcrpc with good performance status and no prior docetaxel chemotherapy ( 有症狀, 身體狀況良好, 未接受過化療 ) Clinicians should offer docetaxel. (Standard)
Taxane-based Chemotherapy Acts on Microtubules and Androgen Receptor Signaling Mol Cancer Ther 2013. 12: 555-566
Slide 7 Presented By Daniel Petrylak at 2014 ASCO Annual Meeting
Slide 8 Presented By Daniel Petrylak at 2014 ASCO Annual Meeting
Slide 9 Presented By Daniel Petrylak at 2014 ASCO Annual Meeting
Docetaxel (TAX 327) Improvement in PSA, Pain and Quality of Life Docetaxel q3w + P Docetaxel q1w + P Mitoxantrone + P PSA decrease 50% p value 45% p=0.0005 48% p<0.0001 32% ref Pain response, % p value 35% p=0.01 31% p=0.07 22% ref QoL improvement*, % p value 22% p=0.009 23% p=0.005 13% ref * > 16 points FACT-P score from baseline; P: prednisone Tannock IF et al. N Engl J Med 2004;351:1502-12
Docetaxel (TAX 327) Survival Benefit Irrespective of Pain All patients Age <68 years Age 69 years No pain Pain KPS 80 KPS 90 No visceral mets Visceral mets Hazard ratio in favor of Docetaxel Mitoxantrone Median OS 17.8 mo 17.6 mo 18.1 mo 21.3 mo 14.2 mo 13.5 mo 21.0 mo 18.9 mo 13.1 mo 0.5 0.7 0.9 1 1.1 1.3 1.4 Berthold D, et al. J Clin Oncol 2008; 26: 242 45
First-line Docetaxel-Estramustine in CRPC: SWOG 9916 PFS OS Petrylak DP, et al: NEJM 351:1513-20, 2004
[TITLE] Presented By Ian Tannock, MD, PhD, FRCPC, DSc at 2013 ASCO Annual Meeting
2-weekly Versus 3-weekly Docetaxel Overall Survival Lancet Oncol. 2013; 14:117-24
美國泌尿學會治療指引 J Urol. 2013 Aug;190(2):429-38 沒有轉移 有轉移 沒有接受過化療 有接受過化療
Index Patient 5: (Symptomatic) mcrpc with good performance status and prior docetaxel chemotherapy ( 有症狀, 身體狀況良好, 有接受過化療 ) Clinicians should offer treatment with abiraterone + prednisone, enzalutamide or cabazitaxel. (Standard)
Cabazitaxel: New Generation Taxane Selected over 450 docetaxel analogues for its ability to overcome taxane resistance Two methoxy groups comprise the difference between docetaxel and cabazitaxel Docetaxel Cabazitaxel Active in vitro and in vivo on tumors resistant to Taxotere 1 1. MitaAC et al, ClinCancer Res. 2009, 15, 723 730
Cabazitaxel Preclinical Summary Docetaxel Cabazitaxel Stabilization of microtubules Activity in taxane-sensitive cell lines Activity in taxane-sensitive in vivo tumor models Crosses blood-brain-barrier in vivo Orally bioavailable in murine models Active in chemotherapy-resistant or insensitive cell lines Active in chemotherapy-resistant or insensitive in vivo tumor models
TROPIC: Phase III Registration Study 146 Sites in 26 Countries mcrpc patients who progressed during and after treatment with a docetaxel-based regimen (N=755) Stratification factors ECOG PS (0. 1 vs. 2) ; Measurable vs. non-measurable disease cabazitaxel 25 mg/m 2 q 3 wk + prednisone for 10 cycles (n=378) mitoxantrone 12 mg/m 2 q 3 wk + prednisone for 10 cydes (n=377) Primary endpoint: OS Secondary endpoints: Progression-free survival (PFS), response rate, and safety Inclusion: Patients with measurable disease must have progressed by RECIST; otherwise must have had new lesions or PSA progression
Primary Endpoint: Overall Survival Median OS (months) MP CBZP 12.7 15.1 Hazard Ratio 0.70 95% CI 0.59 0.83 P value <0.0001 Lancet 2010; 376:1147
Impact of Cabazitaxel on 2-year Survival (updated) Ann Oncol. 2013, 24: 2402 8
Secondary Endpoints Response Rates and Time to Progression (TTP) MP(n=377) CBZP (n=378) Hazard ratio (95% Cl) Tumor assassment Response rate(%) 4.4 14.4 Median TTP (months) 5.4 8.8 0.61(0.49 0.76) PSA assassmant Response rate (%) 17.8 39.2 Median TTP (months) 3.4 6.4 0.75 (0.63 0.90) Pain assessment Response rate(%) 7.7 9.2 Median TTP (months) NR 11.1 0.91(0.69 1.19) Lancet 2010; 376:1147
Subgroup Overall Survival Analysis Factor Subgroup Hazard ratio (95% CI) ITT population All patients 0.70 (0.59 0.83) ECOG status 0, 1 0.68 (0.57 0.82) 2 0.81 (0.48 1.38) Measurable No 0.72 (0.55 0.93) disease Yes 0.68 (0.54 0.85) No. of prior chemo regimens 1 0.67 (0.55 0.83) 2 0.75 (0.55 1.02) Age <65 0.81 (0.61 1.08) 65 0.62 (0.50 0.78) Pain at baseline No 0.57 (0.43 0.77) Yes 0.76 (0.59 0.98) Rising PSA No 0.88 (0.61 1.26) Yes 0.65 (0.53 0.80) Total docetaxel dose <225 mg/m² 0.96 (0.49 1.86) 225 to 450 mg/m² 0.60 (0.43 0.84) 450 to 675 mg/m² 0.83 (0.60 1.16) 675 to 900 mg/m² 0.73 (0.48 1.10) 900 mg/m² 0.51 (0.33 0.79) Progression During last docetaxel treatment 0.65 (0.47 0.90) <3 months since last docetaxel dose 0.70 (0.55 0.91) 3 months since last docetaxel dose 0.75 (0.51 1.11) Favours CBZP Favours MP 0.25 0.5 1 1.5 2 de Bono J, et al. Lancet2010;376:1147 54
美國泌尿學會治療指引 J Urol. 2013 Aug;190(2):429-38 沒有轉移 有轉移 沒有接受過化療 有接受過化療
Index Patient 2: Asymptomatic or minimallysymptomatic mcrpc without prior docetaxel chemo ( 沒有症狀, 身體狀況良好, 沒有接受過化療 ) Clinicians should offer abiraterone+prednisone, docetaxel or sipuleucel-t. (Standard) *2014 新增 : enzalutamide
Docetaxel (TAX 327) Survival Benefit Irrespective of Pain All patients Age <68 years Age 69 years No pain Pain KPS 80 KPS 90 No visceral mets Visceral mets Hazard ratio in favor of Docetaxel Mitoxantrone Median OS 17.8 mo 17.6 mo 18.1 mo 21.3 mo 14.2 mo 13.5 mo 21.0 mo 18.9 mo 13.1 mo 0.5 0.7 0.9 1 1.1 1.3 1.4 Berthold D, et al. J Clin Oncol 2008; 26: 242 45
針對沒有症狀, 身體狀況良好, 沒有接受過化療的 mcrpc 病人 Which Drug For Which Patient? Fact: hard to compare TAX 327, COU-AA-302 and PREVAIL directely - mixed population vs. no/minimal symptom - various metastasis vs. non-visceral mets - active control vs. placebo control - overall survival data is not yet mature in COU-AA-302
Primary Resistance to Abiraterone Acetate in 25% of Patients Primary resistance in 1/4 patients 57 mcrpc patients treated with abiraterone acetate Bone marrow biopsy: Intense AR nuclear expression +CYP17 expression 10% P<0.001 YES 82% responders* (12/13) NO 18% responders (2/12) *NON responders defined as patients treated for 4 months Efstathiou E et al. J Clin Oncol 2011;30:637-43
Short Response to Primary ADT May Guide Treatment Choices Hormonal therapies Retrospective analysis in 108 patients with mcrpc Poor response to subsequent hormonal therapies (including abiraterone, enzalutamide) if time to CRPC with first ADT 16 months (median) Time to CRPC with 1 st -line ADT 16 mo >16 mo PSA 50% 18% 58% Median TTP 3mo 5 mo Median OS - - Loriot Y ASCO GU 2012 (abstract 213) 188 patients with mcrpc in 2 prospective French databases Early castration resistance (CR): progression within 1 st year of ADT High Gleason score & visceral mets more common in early CR Similar benefit to docetaxel irrespective of time to CRPC: Time to CRPC with 1 st- line ADT Docetaxel 1yr >1 yr PSA 50% 67% 81% Median TTP 6.1 mo 7.1 mo Median OS 22.4 mo 36.1 mo Huillard ASCO 2013 (poster)
Initial Gleason Score May Guide Treatment Choice Abiraterone acetate Retrospective analysis 408 patients with mcrpc in real life practice Independent predictors of poor response to abiraterone (multivariate analysis): High Gleason score (8-10) 2 prior chemotherapy lines Post-hoc analysis of TAX327 randomized trial Marked survival benefit with docetaxel q3w in patients with high Gleason score: OS (median) Docetaxel Whole cohort Gleason 7-10 Docetaxel q3w 19.2 mo 18.9 mo (N=185) Mitoxantrone 16.3 mo 14.5 mo (N=164) Survival benefit vs mitoxantrone 2.9 mo 4.4 mo Azria D et al, ASCO GU 2012 (abstract 149) Van Soest R et al Eur Urol. 2013 Aug 11
Visceral Metastases Usually associated with poor prognosis Exclusion criterion in: COU-AA-302 (abiraterone acetate, pre-docetaxel) IMPACT (sipuleucel-t) Chemotherapy may be more helpful
Proposed Decision Tree for Asymptomatic mcrpc Short response (<1 year) to first-line ADT Or high Gleason score (8-10) Or Rapid PSA doubling time Or visceral metastases YES NO Poor predicted response to abiraterone or enzalutamide Good predicted response to hormonal therapies Docetaxel Abiraterone
Molecular States Framework for AR Activation in Prostate Cancer Hormone-sensitive PC Hormone-refractory PC Castrate-resistant PC J Clin Oncol. 2012;30: 644 6
NCCN Guideline Systemic chemotherapy should be reserved for men with mcrpc, in particular those who are symptomatic except when studied in a clinical trial. Certain subsets of patients with mcrpc who have more anaplastic features may benefit from earlier chemotherapy, but this has not been studied adequately in prospective trials.
結論 相較以往, 去勢療法出現抗性的轉移性攝護 癌 (mcrpc) 病人增加許多藥物選擇 Docetaxel 目前仍是有症狀, 身體狀況良好, 未接受過化療的 mcrpc 病人的藥物首選 Cabazitaxel 被證實在曾接受過化療的 mcrpc 病人可延長病患存活期 針對沒有症狀, 身體狀況良好, 沒有接受過化療的 mcrpc 病人, 若預期對新型賀爾蒙的反應不佳, 也可考慮 docetaxel 瞭解化療藥物適用的病人族群及熟悉副作用的處理非常重要
<br /><br />E3805<br />CHAARTED: ChemoHormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer Presented By Christopher Sweeney at 2014 ASCO Annual Meeting
E3805 CHAARTED Treatment Presented By Christopher Sweeney at 2014 ASCO Annual Meeting
Primary endpoint: Overall survival Presented By Christopher Sweeney at 2014 ASCO Annual Meeting
OS by extent of metastatic disease at start of ADT Presented By Christopher Sweeney at 2014 ASCO Annual Meeting
ADT + Docetaxel benefited all subgroups Presented By Christopher Sweeney at 2014 ASCO Annual Meeting
Secondary Endpoints Presented By Christopher Sweeney at 2014 ASCO Annual Meeting
Clinical interpretation Presented By Christopher Sweeney at 2014 ASCO Annual Meeting
謝謝大家 歡迎 問
Denosumab Alpharadin Zoledronic acid Docetaxel Cabazitaxel Sipuleucel-T Enzalutamide Abiraterone 2002 2004 2010 2011 2012 2013 Approval of cabazitaxel (2012) Status in Taiwan Reimbursement of docetaxel (2006) Approval of abiraterone (2013) Reimbursement of zoledronic acid (2007) Reimbursement of denosumab (2013)