2014 Updates on New Treatments f or mCRPC

(1)

2014 Updates on New Treatments f or mCRPC

Yu-Chieh Tsai, MD

( 蔡育傑 )

Medical oncologist

Department of Oncology

National Taiwan University Hospital

(2)

攝護腺癌在台灣的現況 (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%

Many of them experienced mCRPC

資料來源 : 99 年台灣癌症登記報告

(3)

Prostate Cancer Disease Stages 

Presented By Cora Sternberg at 2014 ASCO Annual Meeting

( 土色 : 去勢療法出現抗性 ) ( 桃紅色 : 還對去勢療法有效 )

(4)

Update in ASCO 2014

For Hormone-Sensitive Prostate

Cancer…

(5)

 E3805 CHAARTED: ChemoHormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer

Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

(6)

E3805 – CHAARTED Treatment

(7)

Primary endpoint: Overall survival

(8)

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. The cancer may still respond to other forms of hormone therapy.

American Cancer Society

(9)

Molecular States Framework for AR Activation in Prostate Cancer

J Clin Oncol. 2012;30: 644-6

Hormone-sensitive PC Hormone-refractory PC

Castrate-resistant PC

(10)

Castration-Resistant Prostate Cancer:

AUA Guideline

J Urol. 2013 Aug;190(2):429-38

(11)

Index Patient 3: Symptomatic mCRPC with good perfor mance status and no prior docetaxel chemotherapy

• Clinicians should offer docetaxel.

^(Standard)

(12)

Castration-Resistant Prostate Cancer:

AUA Guideline

J Urol. 2013 Aug;190(2):429-38

(13)

Index Patient 5: (Symptomatic) mCRPC with good perf ormance status and prior docetaxel chemotherapy

• Clinicians should offer treatment with abiraterone + prednison

e, enzalutamide or cabazitaxel.

^(Standard)

(14)

Castration-Resistant Prostate Cancer:

AUA Guideline

J Urol. 2013 Aug;190(2):429-38

(15)

Index Patient 2: Asymptomatic or minimally-symptomat ic mCRPC without prior docetaxel chemo

• Clinicians should offer abiraterone+prednisone, docetaxel or sipuleucel-T.

(Standard)

*2014 新增 : enzalutamide

(16)

Epub on June 1, 2014 in N Engl J Med.

(17)

(18)

Coprimary End Points

(19)

Castration-Resistant Prostate Cancer:

AUA Guideline

J Urol. 2013 Aug;190(2):429-38

(20)

Guideline Statements on Bone Health

• Clinicians should offer preventative treatment (e.g. suppleme ntal calcium, vitamin D) for fractures and skeletal related eve nts to CRPC patients.

(Recommendation)

• Clinicians may choose either denosumab or zoledronic acid w

hen selecting a preventative treatment for skeletal related eve

nts for mCRPC patients with bony metastases.

^(Option)

(21)

Clinical effectiveness of strontium-89 and zoledronic acid in patients with castrate-refractory prostate cancer (CRPC) metastatic to bone receiving docetaxel (TRAPEZE)

Presented By Nicholas James at 2013 ASCO Annual Meeting

(22)

Phase III Study treatments

(23)

Conclusions

(24)

Radium-223 Targets Bone Metastases

Presented By Chris Parker at 2012 Genitourinary Cancers Symposium

(25)

Cell killing and marrow penetration: Two advantages of α-emitters

Presented By Karim Fizazi at 2013 ASCO Annual Meeting

(26)

Cell killing and marrow penetration: Two advantages of α-emitters

Presented By Karim Fizazi at 2013 ASCO Annual Meeting

(27)

Alpha-Particles Cause Lethal Double-Stra nd DNA Breaks

LET, linear energy transfer.

β-emitters ^{• Low-LET}^β radiation

produces single-strand DNA breaks¹

• Single-strand breaks are easily repaired using the opposite strand as a template¹

• Single-strand breaks are less likely to induce cell death¹

α-emitters

• High-LET α -particles produce double-strand DNA breaks^1,2

• Double-strand breaks are difficult to repair^1,2

• Failure to repair double- strand breaks leads to apoptosis (programmed cell death)¹

• Mis-repaired double- strand breaks create

chromosomal aberrations that result in mitotic cell death¹

1. Hall EJ, Giaccia AJ. Radiobiology for the Radiologist. 6th ed. Philadelphia, PA:

Lippincott William & Wilkins; 2006. 2. Bruland OS, et al. Clin Cancer Res.

2006;12(20):6250s-6257s.27

(28)

First clinical experience with Radium-223

Clin Cancer Res. 2005;11: 4451-9

Dosages: 46 (▪), 93 (•), 163 ( ), ▴ 213 ( ), and 250 kBq/kg (♦)▾

Breast cancer (○, n = 10) Prostate cancer (▪, n = 15)

(29)

Radium-223: Phase II Data in HRPC

Lancet Oncol. 2007;8: 587-94

(30)

Radium-223: Phase II Data in HRPC

Lancet Oncol. 2007;8: 587-94

(31)

Radium-223 Improved Overall Survival in the Placebo-Controlled Phase II Study in CRPC

Presented By Chris Parker at 2012 Genitourinary Cancers Symposium

(32)

Phase II Dose-response Study in mCRPC

Eur J Cancer. 2012; 48:678-86

(33)

Pain Index in Different Doses of Radi um-223

5 kBq/kg

(n=26) 25 kBq/kg

(n=24) 50 kBq/kg

(n=20) 100 kBq/kg

(n=23) JONCKHEERE-TERPSTRA TEST FOR TRENDS

Week 2, N 25 23 20 23 P=0.035

Mean (standard deviation) 4.8 (1.4) 4.1 (1.8) 3.9 (1.4) 3.9 (1.6)

Median (min, max) 5.0 (2, 6) 5.0 (1, 6) 4.0 (1, 6) 5.0 (1, 6)

Week 4, N 26 22 19 22 P=0.123

Mean (standard deviation) 4.0 (1.8) 3.9 (1.9) 3.6 (1.6 3.3 (1.8)

Median (min, max) 3.5 (1, 6) 4.0 (1, 6) 4.0 (1, 6) 3.0 (1, 6)

Week 8, N 20 19 18 21 P=0.103

Median (min, max) 5.0 (1, 6) 3.0 (1, 6) 4.0 (1, 6) 2.0 (1, 6)

Week 12, N 20 18 17 20 P=0.717

Median (min, max) 4.0 (1, 6) 3.5 (1, 6) 5.0 (1, 6) 3.0 (2, 6)

Week 16, N 16 16 16 17 P=0.598

Median (min, max) 5.5 (1, 6) 2.0 (1, 6) 5.0 (1, 6) 2.0 (1, 6)

Eur J Cancer. 2012; 48:678-8633

(34)

Phase II Dose-finding Study in mCRPC

Eur Urol 2013;63:189-197

(35)

Phase II Dose-finding Study in mCRPC

Eur Urol 2013;63:189-197

(36)

ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design

Presented By Chris Parker at 2012 Annual Meeting

(37)

37

ALSYMPCA: Endpoints

ALP, alkaline phosphatase; PSA, prostate-specific antigen; SSE, symptomatic skeletal event.

a. See slides (“Other Secondary Efficacy Endpoints”) for more details.

b.Defined as return of total ALP to within normal range at 12 weeks [confirmed by two consecutive measurements ≥2 weeks apart] in patients with total ALP values above upper limit of normal (ULN) at baseline.

c. Defined as ≥25% increase from baseline and an absolute value increase ≥2 ng/mL at ≥12 weeks [in patients with no PSA decline from baseline] or

≥25% increase and an absolute value increase ≥2 ng/mL above nadir confirmed ≥3 weeks later, in patients with an initial decrease from baseline.

SOURCE: Parker C, et al. N Engl J Med. 2013;369(3):213-23.

• Overall survival

PRIMARY ENDPOINT

• Time to total ALP progression^a

• Total ALP response^a

• Time to occurrence of first SSE

• Total ALP normalization^a,b

• Time to PSA progression^a,c

• Other secondary efficacy endpoints^a

• Safety

• Quality of life

SECONDARY ENDPOINTS

Whereas other trials included asymptomatic fractures—detected by means of periodic radiologic review—as

skeletal events, ALSYMPCA had no radiographic review and so only symptomatic pathologic bone fractures were captured. Thus “symptomatic skeletal

event” (SSE) was deemed a more clinically relevant term for this measurement.

(38)

38

SSE V.S SRE

SSE (ALSYMPCA) SRE

Symptomatic Skeletal Event Skeletal Related Event Definition Spinal cord compression Spinal cord compression

Tumor-related orthopedic

Surgical intervention Surgery to bone New symptomatic

pathological fractures Pathological fractures Use of EBRT to relieve skeletal

symptoms Radiation therapy to bone

Hypercalcemia of malignancy

Characteristics No regular radiologic image and more clinical relevant

(39)

Alpha Emitter Radium-223 And Survival I n Metastatic Prostate Cancer

N Engl J Med. 2013;369: 213-23

(40)

ALSYMPCA Updated Analysis Patient Demographics and Baseline Characteristics (ITT N = 921)

(41)

ALSYMPCA Updated Analysis Patient Baseline Characteristics (ITT N = 921)

(42)

ALSYMPCA Updated Analysis Patient Disposition

(43)

ALSYMPCA Updated Analysis Overall Survival

Increase

∆=3.6OS mos

(44)

ALSYMPCA Updated Analysis:

Radium-223 Improved OS Across All Patient Subgroups

SUBGROUP

PATIENTS (n) MEDIAN OS (months)

HR 95% CI

RADIUM-223 PLACEBO RADIUM-223 PLACEBO

All patients 614 307 14.9 11.3 0.70 0.58-0.83

Total ALP

<220 U/L 348 169 17.0 15.8 0.82 0.64-1.07

≥220 U/L 266 138 11.4 8.1 0.62 0.49-0.79

Current use of bisphosphonates

Yes 250 124 15.3 11.5 0.70 0.52-0.93

No 364 183 14.5 11.0 0.74 0.59-0.92

Prior use of docetaxel

Yes 352 174 14.4 11.3 0.71 0.56-0.89

No 262 133 16.1 11.5 0.74 0.56-0.99

Baseline ECOG PS

0 or 1 536 265 15.4 11.9 0.68 0.56-0.82

≥2 77 41 10.0 8.4 0.82 0.50-1.35

Extent of disease

<6 Metastases 100 38 27.0 NE 0.95 0.46-1.95

6-20 Metastases 262 147 13.7 11.6 0.71 0.54-0.92

>20 Metastases 195 91 12.5 9.1 0.64 0.47-0.88

Superscan 54 30 11.3 7.1 0.71 0.40-1.27

Opioid use

Yes^a 345 168 13.9 10.4 0.68 0.54-0.86

No^b 269 139 16.4 12.8 0.70 0.52-0.93

Favors

Radium-223 Favors Placebo

ALP, alkaline phosphatase; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group Performance Status; HR, hazard ratio.

a. Includes patients with a score of 2 or 3 on the World Health Organization (WHO) ladder for cancer pain.

b.Includes patients without pain or opioid use at baseline and patients with a score of 1 on the WHO ladder for cancer pain.

0.5 1.0 2.0

44

(45)

20 0 40 60 80 100

Patients Without SSE, %

Months Since Randomization

0 3 6 9 12 15 18 21 24 27 30

MEDIAN TIME TO SSE (months)

— Radium-223: 15.6

— Placebo: 9.8

HR (95% CI): 0.66 (0.52–0.83) P<0.001

BSoC, Best standard of care; CI, confidence interval; HR, hazard ratio; SSE, symptomatic skeletal event.

— Radium-223 614 496 342 199 129 63 31 8 8 1 0

— Placebo 307 211 117 56 36 20 9 7 4 1 0

45

ALSYMPCA Updated Analysis:

Time to First Symptomatic Skeletal Event

Increase TTSSE

∆=5.8 mos

(46)

Slide 19

(7.4 vs 3.8 months) (3.6 vs 3.4 months)

(47)

Slide 19

(7.4 vs 3.8 months) (3.6 vs 3.4 months)

(48)

ALSYMPCA Updated Analysis AEs of Interest

(49)

ALSYMPCA Updated Analysis AEs of Interest

(50)

EVENT

RADIUM-223 (n = 600) PLACEBO (n = 301)

ALL GRADES,

n (%) GRADE 3,

n (%) GRADE 4,

n (%) GRADE 5,^a

n (%) ALL GRADES,

n (%) GRADE 3,

n (%) GRADE 4,

n (%) GRADE 5,^a n (%) Hematologic AEs

Anemia 187 (31) 65 (11) 11(2) 0 92 (31) 37 (12) 2 (1) 1 (<1)

Thrombocytopenia 69 (12) 20 (3) 18 (3) 1 (<1) 17 (6) 5 (2) 1 (<1) 0

Neutropenia 30 (5) 9 (2) 4 (1) 0 3 (1) 2 (1) 0 0

Nonhematologic AEs

Constipation 108 (18) 6 (1) 0 0 64 (21) 4 (1) 0 0

Diarrhea 151 (25) 9 (2) 0 0 45 (15) 5 (2) 0 0

Nausea 213 (36) 10 (2) 0 0 104 (35) 5 (2) 0 0

Vomiting 111 (19) 10 (2) 0 0 41 (14) 7 (2) 0 0

Asthenia 35 (6) 5 (1) 0 0 18 (6) 4 (1) 0 0

Fatigue 154 (26) 21 (4) 3 (1) 0 77 (26) 16 (5) 2 (1) 0

General physical health deterioration 27 (5) 9 (2) 2 (<1) 5 (1) 21 (7) 8 (3) 2 (1) 2 (1)

Peripheral edema 76 (13) 10 (2) 0 0 30 (10) 3 (1) 1 (<1) 0

Pyrexia 38 (6) 3 (1) 0 0 19 (6) 3 (1) 0 0

Pneumonia 18 (3) 9 (2) 0 4 (1) 16 (5) 5 (2) 2 (1) 0

50

ALSYMPCA Updated Analysis: Safety Profiles Were Similar Betwee n the Radium-223 and Placebo Arms

AE, adverse event.

a. Only 1 grade 5 hematologic AE was considered possibly related to study drug: thrombocytopenia in 1 patient in the radium-223 group.

NUMBER OF PATIENTS WITH AEs OCCURRING IN ≥5% OF PATIENTS IN EITHER TREATMENT GROUP

There were few grade 3 AEs and grade 4 AEs were very low, also comparable to placebo.

(51)

Effect Of Radium-223 Dichloride On Symptomatic Skeletal E vents In Patients With Castration-resistant Prostate Cancer And Bone Metastases: Results From A Phase 3, Double-bli

nd, Randomised Trial.

Lancet Oncol. 2014;15: 738-46

(52)

Time to 1st Symptomatic Skeletal Event,

By Baseline Stratification Factors

(53)

Time to 1st Symptomatic Skeletal Event,

By Baseline Stratification Factors

(54)

Relative Risk Of Individual Symptomatic

Skeletal Event Components

(55)

Relative Risk Of Individual Symptomatic

Skeletal Event Components

(56)

Skeletal Events Occurring In Trials With

Patients With Metastatic CRPC

(57)

OBJECTION HANDLER: v1 Not For Distribution. For Medical Education Only, Not For Promotional Use.

Safety of Cytotoxic Chemotherapy Following Radium-223 Dichlorid e (Rd-223) Therapy

•Number of deaths an d causality during 30 days post Chemo an d limited available he matologic data were similar in both group s

2012 ESMO

(58)

58

Regardless of Age, Ra-223 Prolonged Median Overall Survival

(59)

59

Safety: Radium-223 Was Well Tolerated Across All Age Groups

Incidence of Grade 3/4 Adverse Events According to Age (Safety Population, N=901*)

*Safety population included patients who received at least 1 dose; 1 patient in the placebo group received 1 injection of radium-223 (week 0)

and is included in the radium-223 safety analysis.

SOURCE: Wiechno P, et al. ESMO 2013; Abstract 2883.

(60)

A significantly higher percentage of patients treated with radium-223, versus placebo, experienced a meaningful improvement in quality of life.

60

ALSYMPCA Updated Analysis: A Higher Proportion of Patients Exp erienced Improvement in QOL with Radium-223

FACT-P, Functional Assessment of Cancer Therapy–Prostate.

P = 0.02

0 7 14 21 28

FACT-P Total Score

Placebo Radium-223

-6

-8 -4 -2 0

Mean Change in FACT-P Total Score From Baseline to Week 16

Placebo Radium-223

25

16

-6.8 -2.7

P = 0.006

(61)

1.5-Year Posttreatment Follow-up of Radium-223 Dichloride (Radium-223) in Patients With Castration-Resistant Prostate Cancer (CRPC) and Bone Metastases From the <

br />Phase 3 ALSYMPCA Study

Presented By Sten Nilsson at 2014 Genitourinary Cancers Symposium

(62)

ALSYMPCA Long-term Follow-Up

(63)

Treatment-Related Hematologic AEs

(64)

Nonhematologic Treatment-Related AEs

(65)

Specific Diseases

(66)

Primary Cancers in Other Organs

(67)

• Radium-223, an α-emitter, was shown to significantly prolong overall survival by 3.6 months in CRPC patients with bone m etastases, as compared to placebo.

• All secondary efficacy endpoints were significant and favored radium-223, including time to the first symptomatic skeletal e vent (SSE)

• Radium-223 is well tolerated without clinically meaningful incr ease of hematologic and non-hematologic AEs.

67

Conclusions

(68)

Thank You

(69)

•In ALSYMPCA, radium-223 significantly prolonged overall survival in patients wh o had castration-resistant prostate cancer and bone metastases, with a 30% red uction in the risk of death (HR=0.70), as compared with placebo

•In the updated analysis, the median OS was longer by 3.6 months among patien ts who received radium-223 compared to placebo

•All secondary efficacy endpoints were significant and favored radium-223, includ ing the clinically defined end point of the time to the first SSE

•The overall incidence of AEs (all grade, grade 3/4, SAEs) was consistently lower i n the radium-223 arm than in the placebo group

– The number of patients who discontinued the study drug because of AEs was also lo wer in the radium-223 group

– No clinically meaningful differences in the frequency of hematologic AEs were observ ed between the treatment groups

69

Conclusions

(70)

Conclusions

(71)

New Drugs for mCRPC After 2000

Zoledronic acid

Docetaxel

Sipuleucel-T Abiraterone

Cabazitaxel

Enzalutamide

Alpharadin Denosumab

2002 2004 2010 2011 2012 2013

Reimbursement of docetaxel (2006)

Status in Taiwan

Approval of cabazitaxel (2012)

Approval of abiraterone

(2013)

Reimbursement of denosumab (2013) Reimbursement of

zoledronic acid (2007)

2014 Updates on New Treatments f or mCRPC