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

什麼是mCRPC? 和HRPC有何不同?

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

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)

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)

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)

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

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

對於mCRPC,目前有哪些新藥?作用機轉為何?

Approved New Drugs for mCRPC Denosumab Alpharadin Docetaxel Enzalutamide Cabazitaxel Zoledronic acid Abiraterone Sipuleucel-T 2002 2004 2010 2011 2012 2013 即便有很多新藥，攝護腺癌治療的中心還是賀爾蒙!!

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

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

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

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

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

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

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 />

Taxane-based Chemotherapy Acts on Microtubules and AR Signaling Docetaxel Cabazitaxel Mol Cancer Ther 2013. 12: 555-66

Radium-223 Is a Unique α-Emitter x4 x2

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

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

這些新藥能延長生命嗎? 能減輕痛苦嗎?

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; 32:3436-48

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; 32:3436-48

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; 32:3436-48

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

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

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?

Approved New Drugs for mCRPC Denosumab Alpharadin Docetaxel Enzalutamide Cabazitaxel Zoledronic acid Abiraterone Sipuleucel-T 2002 2004 2010 2011 2012 2013 Reimbursement of docetaxel (2006) Status in Taiwan Approval of cabazitaxel (2012) Reimbursement of abiraterone (2014) Reimbursement of denosumab (2013) Reimbursement of zoledronic acid (2007)

Docetaxel : 健保規定 1.於荷爾蒙治療失敗之轉移性前列腺癌。

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。

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

Abiraterone(澤珂)的建議劑量及服藥方式

Hormone Concentration After Abiraterone Acetate J Clin Oncol. 2008; 26:4563-71

Hormone Concentration After Abiraterone Acetate + Dexamethasone J Clin Oncol. 2008; 26:4563-71

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。

臨床上如何選擇適合的mCRPC藥物?

J Urol. 2015 Feb;193:491-9

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-223. (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)

J Urol. 2015 Feb;193:491-9

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)

J Urol. 2015 Feb;193:491-9

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)

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

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

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。

謝謝聆聽 歡迎討論