1. Chemohormonal Therapy: New Paradigm in the Treatment of Metastatic Prostate Cancer — Why, When, and How? Chemohormonal Therapy: New Paradigm in the Treatment of Metastatic Prostate Cancer — Why, When, and How? 馮思中 教授 長庚紀念醫院泌尿腫瘤科

2. Targeting prostate cancer cell with different mechanisms of action

3. [TITLE] Presented By William K. Oh, MD at 2013 ASCO Annual Meeting 攝護腺癌病人的自然病史 局部治療 開始荷爾蒙治療 化療 標準去勢治療 Denosumab 、 Zoledronic Acid 鐳 -223 Enzalutamide Abiraterone 澤珂錠 去勢治療 抗雄性素後續治療 Sipuleucel-T 歐洲紫杉醇 第二代歐洲紫杉醇 化療後 死亡 時間 病情進展 /PSA 值 開刀／放射 化療 ?

4. COU-AA-302 Median overall survival was significantly longer in the abiraterone acetate group than in the placebo group (34·7 months [95% CI 32·7–36·8] vs 30·3 months [28·7–33·3]; hazard ratio 0·81 [95% CI 0·70–0·93]; p=0·0033). Lancet Oncology Volume 16, No. 2, p152–160, February 2015 Phase III clinical trials in mCRPC treatment

5. PREVAIL

6. In addition to improving overall survival relative to placebo, enzalutamide significantly improves patient-related outcomes and delays occurrence of first skeletal-related event in chemotherapy- naive men with metastatic castration-resistant prostate cancer.

7. What is the best treatment sequence for CRPC? OS range from 7.1 to 15.8m Phase III trial needed to find out what is the best sequence of treatment.

8. Early use of chemotherapy in prostate cancer: is this rationale?

9. 1.The use of early chemotherapy may address the phenotypically heterogeneous subpopulation of tumor cells and eliminate androgen-independent clones, allowing for a potentially improved therapeutic effect. 2. The early use of cytotoxic chemotherapy may improve outcomes by attacking clones resistant to ADT before they expand or acquire more resistance or simply killing more cancer cells when they are more vulnerable 3. Therapy works best when it is multitargeted, administered in a lesser disease volume as a preemptive strike before adaptive resistance. Other potential factors include better drug tolerance and less toxicity in less sick patients. Why chemo-hormonal work better? asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK e263

11. high-volume disease: visceral metastasis and/or four or more bone metastases with at least one beyond axial skeleton (pelvis and vertebral column).

12. Comparison of AFU 15 and E3805 trial Concerns regarding AFU 15 trial: 1.Relatively small sample size 2.Substantial percentage of patients with good prognostic factors at baseline: 49% in the ADT plus docetaxel group and 50% in ADT alone. 3.High toxicity reported, > 10% incidence of grade 3 neutropenia and four deaths in ADT plus docetaxel; 21% discontinued in docetaxel plus ADT group 4. Cross-over treatments: 62% of patients given ADT alone received docetaxel at progression, compared with 28% of patients given ADT plus docetaxel who were re-treated with docetaxel. asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK e263

13. Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE)

15. Median survival was increased by 10m from 67m on SOC to 77m on SOC+D

16. Adjuvant chemotherapy improves overall survival in high-risk, localized prostate cancer—ASCO 2015 Results: The 4-year OS rates were 89% for men who received ADT and RT versus 93% for men treated with ADT, RT, and docetaxel (HR = 0.70; 90% CI, 0.51- 0.98; P = 0.04). 5-year disease-free survival rates were 66% in the standard therapy group versus 73% in the docetaxel group (HR = 0.76; 95% CI: 0.57- 1.00; P =.05)

17. Integration of copy number and transcriptomics provides risk stratification in prostate cancer: A discovery and validation cohort study. EBioMedicine, 2015; DOI: 10.1016/j.ebiom.2015.07.017 Prostate cancer is five different diseases, experts say

18. Conclusion Many drugs are currently available for CRPC therapy. New evidences suggested that early chemotherapy may be beneficial for certain hormone naïve metastasis prostate cancer (mPca). The best treatment algorithm for mPCa has yet to be determined.

19. Thank you