The Role of the Medical Oncologist in the Treatment of Prostate Cancer

Daniel P. Petrylak, MD Professor of Medicine Columbia University Medical Center

When should you see an oncologist?

• High risk localized disease • Rising PSA after local therapy • Hormone sensitive disease • Endocrine Resistant Disease

Natural History of Metastatic Prostate Cancer Tumor Volume and Activity

Castration Secondary Hormonal Rx Chemo Rx

Time

Ligand activated androgen receptor signaling remains a ‘driver’ in CRPC

•

Hypothesis:

• Hormone-refractory prostate cancer (HRPC) frequently remains driven by a ligand-activated androgen receptor (AR).

• This disease is not truly hormone refractory

Biological evidence for a continued hormone ‘driver’ in CRPC

• High intratumoral androgens despite castration • Castration resistance: – AR amplification/ mutations in CRPC increase AR activity – ↑ AR mRNA expression alone → resistance in isogenic lines – Aberrant activation of the androgen receptor

Abiraterone: Response

Response Parameter Untreated Prior Docetaxel PSA >50%: >30%: 38/54 (70%) 18/34(47%) 43/54 (80%) 22/34 (65%) TTP PSA 231 days 161 days RECIST 15/29(60%) NR

Abiraterone Clinical Trials

• Abiraterone vs placbo in patients with CRPC prior to docetaxel • Abiraterone/prednisone vs placebo/prednisone in CPRC patients post chemotherapy. Close to accrual

Waterfall Plot of Best Percent PSA Change from Baseline

Chemotherapy-Naïve (N=65) Post-Chemotherapy (N=75) 62% (40/65) >50% Decline 51% (38/75) >50% Decline

AFFIRM

P hase 3 Registration Trial of MDV3100 in Post-Chemotherapy CRPC Patients

MDV3100 – 240 mg QD

2 R

Placebo QD

1

Primary Endpoint: Sample size: Statistics: Biomarkers: 25% survival increase (12 to 15 months) ~1170 (780 and 390) 85% Power; p=0.05, two-sided CTC enumeration and profiling with outcome

Scher, H. (North America) and De Bono, J. Co-PI, Medivation

When is chemotherapy initiated?

• At first PSA rise in non metastatic patients • At PSA rise in an asymptomatic patient • At PSA rise and scan progression in an asymptomatic patient • In a patient with symptomatic bone pain

Docetaxel HRPC Trials

TAX 327 1 N=1006 SWOG 9916 N=770 2 Mitoxantrone 12 mg/m 2 Prednisone 10 mg q day Q 21 days up to 10 cycles Docetaxel 30 mg/m 2 /wk Prednisone 10 mg q day 5 on; 1 off x 6 cycles Docetaxel 75 mg/m 2 Prednisone 10 mg q day Q 21 days up to 10 cycles Mitoxantrone Prednisone

12 mg/m 5 mg bid 2 Q 21 days

Docetaxel

60 mg/m 2 d 2

Estramustine

280 mg d1-5*

Dexamethasone

20 mg, tid d 1 & 2 *Warfarin and aspirin

1. Tannock et al. N Engl J Med 2004:351;1502-1512. 2. Petrylak et al. N Engl J Med 2004;351:1513-1520.

100% 80% 60% 40% 20% 0% 0

Overall Survival

D+E M+P # at Risk 338 336 # of Deaths 217 235 Median in Months 18 16 HR: 0.80 (95% CI 0.67, 0.97), p = 0.01

12 Months 24 36

Petrylak et NEJM 2004

48

Overall Survival — TAX 327 1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 Combined: D 3 wkly: D wkly: Mitoxantrone 6 Median survival (mos) 18.2

18.9

17.3

16.4 12 Hazard ratio P-value 0.83

0.76

0.91

– 0.03

0.009

0.3

– Months 18 Tannock et al. N Engl J Med 2004:351;1502-1512.

24 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone 30

Evidence for Angiongenis as a Target for Prostate Cancersis

• Microvessel density correlates with prognosis in radical prostatetectomy specimens • Elevated levels of VEGF correlate with prognosis in CRPCa • bFGF expresse in epithelial and stromal cells

CALGB Study

• Primary endpoint of improvement in median survival from 19 in docetaxel arm to 23 months in docetaxel/bevizcuzimab arm not met Press Release Roche 2010

CALGB 9040 : Randomized Double Blinded Placebo controlled Phase III Trial Comparing Docetaxel + Prednisone with or without Bevacizumab in men with HRPC

Eligibility •Metastatic PC •T <50 ng/ml •No prior chemo •Adequate hem, renal & liver function Stratification

Halabi

nomogram

Arm A Dexamethasone Docetaxel Prednisone Placebo* Arm B Dexamethasone Docetaxel Prednisone Bevacizumab*

8 mg po x 3 doses 75 mg/m 2 on d1 q21d 10 mg po daily IV on day 1 q 21 days 8 mg po x 3 doses 75 mg/m 2 on d1 q 21d 10 mg po daily 15 mg/kg IV on day 1q 21d N = 1020 patients CALGB, ECOG, NCIC

Structure of Thalidomide and the 2nd-Generation IMiDs

100 90 80 70 60 50 40 30 20 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100

Best response by % change in PSA

No prior chemotherapy Prior chemotherapy

MAINSAIL TRIAL Screening

•

Metastatic CRPC

•

Chemo-naïve

•

Disease Progression CRPC Patients N= 1,015 Randomize 1:1 Docetaxel/Prednisone + Lenalidomide Until Progression or Toxicity N

~

500 Docetaxel/Prednisone + Placebo Until Progression or Toxicity N

~

500 Follow-Up:

•

For Survival

•

For Other Treatments

•

Up to five years

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/m² q 3 wk + prednisone * for 10 cycles (n=378) * Oral prednisone/prednisolone: 10 mg daily.

Primary endpoint:

OS

Secondary endpoints:

Progression-free survival (PFS), response rate, and safety mitoxantrone 12 mg/m² q 3 wk + prednisone * for 10 cycles (n=377)

Inclusion:

Patients with measurable disease must have progressed by RECIST; otherwise must have had new lesions or PSA progression 2 3

Pre-Protocol Treatments

MP (n=377) CBZP (n=378) Total prior docetaxel dose (mg/m²)

Median

Months from last docetaxel dose to progression

Median

Number of patients progressed (%)

During last docetaxel treatment <3 months since last docetaxel dose ≥3 months since last docetaxel dose 529.2

0.70

27.6

48.0

24.0

576.6

0.80

30.4

41.8

27.0

Radiation (%)

Curative Palliative

Chemotherapy (%)

1 regimen 2 regimens ≥3 regimens 29.7

29.2

71.1

21.0

8.0

25.9

35.4

68.8

24.9

6.3

2 4

Primary Endpoint: Overall Survival

Proportion of OS (%) 100

(ITT

Analysis)

80 60 Median OS (months) Hazard Ratio 95% CI P-value MP CBZP

12.7

15.1

0.70

0.59–0.83

<.0001

40 20 Number at risk MP CBZP 0 0 months

377 378

6 months

300 321

12 months

188 231

18 months

67 90

24 months

11 28

30 months

1 4 2 5

On-Study Laboratory Abnormalities Safety Population

MP (n=371) All Grades (%) Grade ≥3 (%) CBZP (n=371) All Grades (%) Grade ≥3 (%) Hematology Anemia Leukopenia Neutropenia Thrombocytopenia Biochemistry

Alkaline Phosphatase ALAT ASAT Hyperbilirubinemia Creatinine 81.4

92.5

87.6

43.1

57.7

18.9

28.0

4.6

11.6

4.9

42.3

58.0

1.6

9.7

0.3

0.5

0.8

0.5

97.3

95.7

93.5

47.4

53.6

25.9

27.8

3.8

15.6

10.5

68.2

81.7

4.0

7.3

1.1

0.8

0.5

1.3

2 6

Total Deaths During Study Safety Population

Total deaths during study Due to progression Due to AEs Due to other reasons MP (n=371)

275 (74.1%) 253 (68.2%) 7 (1.9%) 15 (4.0%)

CBZP (n=371)

227 (61.2%) 197 (53.1%) 18 (4.9%) 12 (3.2%) 2 7

Zometa 039: Skeletal-Related Event (SRE) Prevention Study

Bone metastases with progressive disease after ADT (N=639) Randomize Standard Care + ZOMETA Endpoint: SRE Standard Care + Placebo

Skeletal-Related Events

• • • •

Pathologic fracture Spinal cord compression/vertebral body collapse Radiation or surgery to bone Change in antineoplastic therapy

Proportion of Patients With SRE (-HCM) at Month 15 by Treatment (Intent-to-Treat Patients)

Proportion of Patients With SRE 0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0 38% ZOMETA 8/4 mg * 34% ZOMETA 4 mg 45% Placebo *

P

<.05 vs placebo

Time to First SRE (–HCM) by Treatment

% Patients Without the Event 110 100 90 80 70 60 50 40 30 20 10 0 0 ZOMETA 4 mg Placebo Median Time, Days* NR 321 50 100 150 200 250 300 350 400 Time After the Start of Study Drug (Days) 450 500 550 *

P

=.011 ZOMETA 4 mg vs placebo

Study Design: International, Randomized, Double Blind, Active-Controlled Study Key Inclusion

•

Hormone-refractory (castration resistant) prostate cancer and bone metastases Key Exclusion

•

Current or prior IV bisphosphonate treatment Denosumab 120 mg SC Zoledronic acid 4 mg IV and Placebo IV* every 4 weeks (N = 950) * and Placebo SC every 4 weeks (N = 951)

• • •

Calcium and Vitamin D supplemented in both treatment groups Accrual period from May 2006 to December 2008 Analysis cut-off date October 2009 *Per protocol and Zometa ® label, IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine. No SC dose adjustments made due to increased serum creatinine.

Time to First On-Study SRE 1.00

0.75

HR 0.82 (95% CI: 0.71, 0.95) P = 0.0002 (Non-inferiority) P = 0.008 (Superiority) 18% Risk Reduction 0.50

0.25

0 0 Subjects at risk: Zoledronic Acid Denosumab 951 950 3 733 758 Denosumab Zoledronic acid KM Estimate of Median Months 20.7

17.1

6 544 582 9 12 15 Study Month 407 472 299 361 207 259 18 140 168 21 93 115 24 64 70 27 47 39

Conclusions

• Standard of care for CRPCA is docetaxel/prednisone • Novel phase IIII studies are combining docetaxel with novel targeted agents • Carbazitaxel is approved as a second line therapy for castration resistant prostate cancer • New biological approaches are being evaluated in the second line setting

Questions

• Prostate cancer after hormone ablation is A) Still hormone responsive B) Does not respond to chemotherapy C) Spreads to the bone in 90% of pateints D) A and C

Question 2

• A significant complication of treatments targeting bone (bisphosphophonates and denosamab) is A) Osteonecrosis of the jaw B) Hand foot syndrome C) Rash D) Diarrhea