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Sequential and Combination Therapy for mCRPC : What Do We Have and How Do We Apply? 台大醫院腫瘤醫學部 蔡育傑醫師.

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Presentation on theme: "Sequential and Combination Therapy for mCRPC : What Do We Have and How Do We Apply? 台大醫院腫瘤醫學部 蔡育傑醫師."— Presentation transcript:

1 Sequential and Combination Therapy for mCRPC : What Do We Have and How Do We Apply?
台大醫院腫瘤醫學部 蔡育傑醫師

2 什麼是mCRPC? 和HRPC有何不同?

3 HRPC versus CRPC Hormone-refractory prostate cancer (賀爾蒙無效的攝護腺 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 護腺癌,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 -> mCRPC是指”有轉移”的CRPC American Cancer Society

4 Prostate Cancer Disease Stages<br />
(桃紅色: 還對去勢療法有效) (土色: 去勢療法出現抗性) 轉移性攝護腺癌,去勢療法有效 Prostate Cancer Disease Stages<br /> 攝護腺局部 局部治療後PSA上升 去勢療法無效的非轉移性攝護腺癌 去勢療法無效的轉移性攝護腺癌(mCRPC)

5 去勢療法出現抗性的攝護腺癌(CRPC) 歐洲泌尿醫學會(EAU)在2010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) Three consecutive rises of PSA, 1 week apart, resulting in two 50% increases over the nadir, with a PSA > 2 ng/mL (每隔一週,連續三次血清中PSA值增加50% ) Anti-androgen withdrawal for at least 4 weeks for flutamide and for at least 6 weeks for bicalutamide (口服男性賀爾蒙對抗治療停止達4週或以上) PSA progression, despite consecutive hormonal manipulations (使用第二線荷爾蒙治療,血清中PSA值仍持續增加)

6 去勢療法出現抗性的攝護腺癌(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) (PSA增加) or Radiological progression (The appearance of two or more bone lesions on bone scan or enlargement of a soft tissue lesion using RECIST) (影像上惡化的證據)

7 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

8 Molecular States Framework for AR Activation in Prostate Cancer
Hormone-sensitive PC Hormone-refractory PC Abiraterone Enzalutamide Hormone Non-Hormone Drug例如化療 Castrate-resistant PC J Clin Oncol. 2012;30: 644-6

9 對於mCRPC,目前有哪些新藥?作用機轉為何?

10 Approved New Drugs for mCRPC
Denosumab Alpharadin Docetaxel Enzalutamide Cabazitaxel Zoledronic acid Abiraterone Sipuleucel-T 即便有很多新藥,攝護腺癌治療的中心還是賀爾蒙!!

11 1966年諾貝爾醫學獎得主 “for his discoveries concerning hormonal treatment of prostatic cancer” (因為他在攝護腺癌賀爾蒙治療的發現..) Charles Brenton Huggins

12 傳統上賀爾蒙治療的策略 減少血液中雄性素 - 睪丸切除 阻止雄性素與雄性素受體結合 - 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

13 mCRPC病人賀爾蒙治療的策略 減少血液中雄性素 - 睪丸切除 阻止雄性素與雄性素受體結合 - 作用在下視丘的藥物減少對睪丸的刺激
(打針: Leuplin, Diphereline, Zoradex) - 抑制腎上腺分泌雄性素 (二側腎上腺切除, 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

14 正常情況下雄性素分泌的比例 腎上腺 性腺功能正常的男性 攝護腺腫瘤 睪丸 大約 10% 的雄性素 才是由腎上腺所分泌
大部分雄性素於睪丸內合成 (約 90%) 睪丸 Ref: Zytiga monograph

15 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 睪丸 大部分雄性素於睪丸內合成 (約 90%)
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

16 Sites of Action by Androgen Biosynthesis Inhibitors
Abiraterone: 阻斷腎上腺及攝護腺癌細胞內雄性素的生成 J Clin Oncol. 2011;29:3651-8

17 Enzalutamide: 阻斷雄性素受體功能
<br />Enzalutamide an AR signalling inhibitor: targets multiple steps in the (AR) signaling pathway<br />

18 Taxane-based Chemotherapy Acts on Microtubules and AR Signaling
Docetaxel Cabazitaxel Mol Cancer Ther :

19 Radium-223 Is a Unique α-Emitter
x4 x2

20 Karim Fizazi, MD, PhD at 2013 ASCO Annual Meeting
[TITLE] Karim Fizazi, MD, PhD at 2013 ASCO Annual Meeting

21 Principle of Sipuleucel-T
(PA2024) - Patients receive 3 leukapheresis procedures (at weeks 0, 2, and 4) and infusion of sipuleucel-T or placebo 3 days later Nat Rev Immunol. 2010; 10:580-93

22 這些新藥能延長生命嗎? 能減輕痛苦嗎?

23 mCRPC Recommendations
Androgen-Deprivation Therapy雄性素去除療法: Continuous androgen deprivation (pharmaceutical or surgical) should be continued indefinitely regardless of additional therapies (Therapies in Addition to Androgen-Deprivation Therapy) Therapies with demonstrated survival and quality-of-life benefits可延長存活期與提升生活品質: Abiraterone acetate Enzalutamide Radium-223 in patients with bone metastases. Docetaxel J Clin Oncol. 2014; 32:

24 mCRPC Recommendations
Therapies with demonstrated survival benefit and unclear quality-of-life benefit可延長存活期: Sipuleucel-T in asymptomatic or minimally symptomatic p’t Cabazitaxel in p’t progressed after docetaxel Therapies with quality-of-life benefit without demonstrated survival benefit可提升生活品質: Mitoxantrone Therapies with biologic activity and unknown survival or quality-of-life benefit療效不明: Antiandrogens (eg, bicalutamide, flutamide, nilutamide) may be offered. Ketoconazole may be offered Low-dose corticosteroid monotherapy may be offered J Clin Oncol. 2014; 32:

25 mCRPC Recommendations
Therapies without demonstrated survival or quality-of-life benefit過去臨床試驗證實無效者: Bevacizumab Estramustine Sunitinib Palliative Care Services緩和醫療 Palliative care should be offered to all patients, particularly to those exhibiting symptoms or quality-of-life (QOL) decrements, regardless of treatment type J Clin Oncol. 2014; 32:

26 New Drugs for Patient with mCRPC after Docetaxel
Therapy Disease State Study (Patient No.) Control arm Hazard Ratio Survival (months) Survival diff. (months) Cabazitaxel + prednisone Post-Docetaxel TROPIC (N=755) Mitoxantrone Prednisone 0.70 15.1 vs 12.7 2.4 Abiraterone COU-AA-301 (N=1195) Placebo 0.74 15.8 11.2 4.6 Enzalutamide AFFIRM (N=1199) 0.63 18.4 13.6 4.8 Radium-223 ALSYMPCA (N=809) 14.9 11.3 3.6 Sipuleucel-T Mild or minimal symptoms (1st line and 2nd line) IMPACT (N=512) control (sham op) 0.78 25.8 21.7 4.1

27 New Drugs for Patients with Chemo-naive mCRPC
Therapy Disease State Study (Patient No.) Control arm Hazard Ratio Survival (months) Survival diff. (months) Docetaxel + prednisone with or without symptoms TAX 327 (N=1006) Mitoxantrone+ Prednisone 0.79 19.3 vs 16.3 3.0 Abiraterone+ No or mild symptoms COU-AA-302 (N=1088) Placebo 0.81 34.7 30.3 4.3 Enzalutamide Asymptomatic or mildly symptomatic PREVAIL (N=1717) 0.71 32.4 30.2 (estimated) - Sipuleucel-T Mild or minimal symptoms (1st line and 2nd line) IMPACT (N=512) Placebo control (sham op) 0.78 25.8 21.7 4.1

28 這些新藥國內已經上市了嗎? 健保的給付規定?怎麼用呢?
這些新藥國內已經上市了嗎? 健保的給付規定?怎麼用呢?

29 Approved New Drugs for mCRPC
Denosumab Alpharadin Docetaxel Enzalutamide Cabazitaxel Zoledronic acid Abiraterone Sipuleucel-T Reimbursement of docetaxel (2006) Status in Taiwan Approval of cabazitaxel (2012) Reimbursement of abiraterone (2014) Reimbursement of denosumab (2013) Reimbursement of zoledronic acid (2007)

30 Docetaxel : 健保規定 1.於荷爾蒙治療失敗之轉移性前列腺癌。

31 Abiraterone : 健保規定 1. 治療藥物或手術去勢抗性的轉移性前列腺癌(ECOG分數須≦2)且已
使用過docetaxel 2個療程以上且治療無效者。 2. 需與prednisone或prednisolone併用。 3. 須經事前審查核准後使用,每3個月需再次申請。

32 Docetaxel的副作用 Neutropenia : 與劑量有關 (標準劑量為75mg/m2)
Fluid retention syndrome - edema, weight gain, 3rd space fluid collection - 累積劑量 > 400mg/m2 較易發生 - 預防 : 口服或注射steroid Hypersensitivity : 比paclitaxel少 Dermatologic: skin rash, alopecia, nail damage Neuropathy

33 Abiraterone(澤珂)的建議劑量及服藥方式

34 Hormone Concentration After Abiraterone Acetate
J Clin Oncol. 2008; 26:

35 Hormone Concentration After Abiraterone Acetate + Dexamethasone
J Clin Oncol. 2008; 26:

36 Abiraterone的副作用 Abiraterone的作用機轉會促使體內礦物皮質激素濃度升高, 並可能導致高血壓、低血鉀和體液滯留。和類固醇併用,可 降低這些不良反應的發生率與嚴重度。 原本患有心臟衰竭、最近曾發生心肌梗塞,或患有心室心律 不整的病 患,可能會因藥物影響,導致血壓升高、低血鉀 或體液滯留,而使病 況惡化,所以接受治療時應特別留意, 應至少每個月接受一次監測。 有少部分會出現肝功能指數(ALT或 AST)異常升高的現象, 而且通常發生在開始治療後的最初3個月內。 治療前指數就 異常升高的病人,比較容易出現肝功能異常。

37 臨床上如何選擇適合的mCRPC藥物?

38 J Urol Feb;193:491-9

39 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 & Radium (Standard) Clinicians may offer abiraterone+prednisone. (Recommendation) Clinicians may offer ketoconazole+steroid, mitoxantrone or radionuclide therapy to patients who do not want or cannot have one of the standard therapies. (Option)

40 J Urol Feb;193:491-9

41 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, cabazitaxel or Radium-223. If the patient received abiraterone+prednisone prior to docetaxel chemotherapy, he should be offered cabazitaxel or enzalutamide. (Standard) Clinicians may offer ketoconazole+steroid if abiraterone + prednisone, cabazitaxel or enzalutamide is unavailable (Option) Clinicians may offer re-treatment with docetaxel to patients who were benefitting at the time of discontinuation (due to reversible side effects) of docetaxel chemotherapy. (Option)

42 J Urol Feb;193:491-9

43 Index Patient 2: Asymptomatic or minimally-symptomatic 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 Clinicians may offer first-generation antiandrogen therapy, ketoconazole + steroid or observation who do not want or cannot have one of the standard therapies. (Option)

44 Proposed Decision Tree for Asymptomatic mCRPC (Clinical factor)
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

45

46

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48 Common Drug Combination in mCRPC
維持雄性素去除療法ADT (通常為LH-RH agonist如 Leuplin/Zoladex或睪丸切除) Bone-targeting therapy包括Radium 223 合適的使用化療藥物(docetadel, cabazitaxel)或新型賀 爾蒙 (abiraterone, enzalutamide) - 新藥間如何併用尚未有定論

49 結論 相較以往,去勢療法出現抗性的轉移性攝護腺癌(mCRPC) 病人增加許多藥物選擇。
- 健保有給付的: Docetaxel、Abiraterone - 可自費使用的: Cabazitaxel 瞭解藥物適用的病人族群及熟悉副作用的處理非常重要。

50 謝謝聆聽 歡迎討論


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