Elderly men with prostate cancer + ADT

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Phyllis Elliott
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2 Elderly men with prostate cancer + ADT

3 Background and Rationale

4 ADT and Osteoporosis

5 Proportion of Patients With Fractures 1-5 Yrs After Cancer Diagnosis %; P < No ADT (n = 20,035) ADT (n = 6650) Frequency (%) Any Fracture Shahinian VB, et al. N Engl J Med. 2005;352: %; P < Fracture Resulting in Hospitalization

6 Bone metastases

7 Bone metastases > 90% of patients with metastatic CRPC have radiologic evidence of bone metastases 1 Skeletal-related events (SREs) include spinal cord compression, pathological fracture, and need for surgery or EBRT 2 Bone metastases are a major cause of death, disability, decreased quality of life, and increased treatment cost 3 1. Tannock et al. N Engl J Med. 2004;351: Lipton. Semin Oncol. 2010;37:S15-S Lange and Vasella. Cancer Metastasis Rev. 1999;17:

8 Lumbar spine MRI

$Skeletal-related events in metastatic prostate cancer Patients (%) Total SREs Pathologic fracture Radiation therapy Surgical$

9 Skeletal-related events in metastatic prostate cancer Patients (%) Total SREs Pathologic fracture Radiation therapy Surgical intervention Spinal cord compression 24-month data of the placebo arm of a randomized trial; n=208 Saad F, et al. J Urol, 2003.Abstract 1472.

10 Bone lesions are associated with worse survival No bone lesions <6 bone lesions >6 bone lesions Cumulative survival Months Pezaro C et al. Eur Urology In press Attard G, Multidisciplinary approach to castration-resistant prostate cancer. Presented at ECC 2013.

11 MDT approach Urologist Radiotherapist Surgeon Medical oncologist Nuclear medicine physician

Resting New bone Osteoclasts Mononuclear cells Osteoblasts Mineralized

12 Normal Bone Remodeling Relies on the Balance Between the Activities of Osteoblasts and Osteoclasts Normal bone remodeling Reversal Resorption Resting New bone Osteoclasts Mononuclear cells Osteoblasts Mineralized bone matrix Adapted from Coxon JP, et al. Prostate Cancer Prostatic Dis. 2004;7:

The Vicious Cycle of Bone Metastases in CRPC CTXI, ICTP, Bone-derived

cells Osteoblastic factors (ET-1, BMP, IGFs, FGF, upa, TGF-β) Growth

Osteoblasts Mineralized bone matrix CRPC bone metastases are

of type I collagen; PTHrP, parathyroid hormone related protein; upa,

13 The Vicious Cycle of Bone Metastases in CRPC CTXI, ICTP, Bone-derived growth factors (TGF-β) Osteolytic factors (PTHrP/IL-6) Prostate cancer cells Osteoblastic factors (ET-1, BMP, IGFs, FGF, upa, TGF-β) Growth factors (ALP, PINP, Unknown GFs) RANKL RANKL RANKL Osteoclasts New bone Osteoblasts Mineralized bone matrix CRPC bone metastases are predominantly osteoblastic ET, endothelin; ICTP, C-terminal telopeptides of type I collagen; PTHrP, parathyroid hormone related protein; upa, urokinase-type plasminogen activator. Adapted from Kingsley LA, et al. Mol Cancer Ther. 2007;6:

14 The vicious cycle of bone metastases 1. Sources of RANKL include osteoblasts, stromal cells and T lymphocytes. 2. OPG, released by ostoblasts progenitors, binds to RANKL preventing it from interacting with RANK on osteoclasts. 3. Prostate cancer cells produce osteoclastic factors Benjamin A. Gartrell & Fred Saad: Nature Reviews Clinical Oncology 11, (2014)

15 Bone Metastasis Targeted Therapies: Capitalizing on the Altered Microenvironment Existing therapies for bone metastasis γ-rays: EBRT Bisphosphonates Denosumab β-emitters: Strontium-89, samarium-153 α-emitter: Radium 223 Interfere with deregulated signaling pathways to/from the bone Target the bone and actively kill the tumor cells 1. Saad F, et al. J Natl Cancer Inst. 2002;94(19): Saad F, et al. J Natl Cancer Inst. 2004;96(11): Horwich A, et al. Ann Oncol. 2013;Jun 27[Epub ahead of print].

16 Radium-223 Has a Targeted Mechanism of Action Targets new bone, e.g. bone metastases Irradiates adjacent tumor cells leading to highly localized tumor cell killing

[ 18 F] FDG PET/CT at Baseline and After 2 1njections of Ra-223 Baseline Bone Scan Baseline [1 8 F) FDG

[1 8 F) FDG PET/CT ( Response ( No Response Fused [1 8 F) FDG PET/CT After 2 lnjections of Ra-223 Response

baseline) in [1 8 F) FDG uptake intensity in mult iple bone mets located in the thoracic and lumbar spine,

17 [ 18 F] FDG PET/CT at Baseline and After 2 1njections of Ra-223 Baseline Bone Scan Baseline [1 8 F) FDG PET [1 8 F) FDG PET After 2 lnjections of Ra-223 ( Response Baseline Fused SPECT/CT ) ) ) Baseline Fused [1 8 F) FDG PET/CT ( Response ( No Response Fused [1 8 F) FDG PET/CT After 2 lnjections of Ra-223 Response Images obtained after 2 injections of Ra-223 showed a significant decrease ( 25% decrease of SUVmaxfrom baseline) in [1 8 F) FDG uptake intensity in mult iple bone mets located in the thoracic and lumbar spine, indicating a partial metabolic treatment response at the level of the tumor cells early during Ra-223 therapy.

Therapies That Interfere With Deregulated

Provides palliative effect Baron R, et al.

18 Therapies That Interfere With Deregulated Signaling Pathways to/from the Bone Denosumab RANKL Denosumab RANK Bisphosphonates Bisphosphonates Binds to RANKL and prevents it from binding to RANK on the surface of cells Bind to bone mineral and are taken up by mature osteoclasts at sites of bone resorption Loss of osteoclast formation, function, and survival Loss of resorptive function Provides palliative effect Baron R, et al. Bone. 2011;48(4): No survival benefit has been demonstrated

19 Elderly men with prostate cancer

20 Pamidronate vs Placebo in Metastatic Prostate Cancer Skeletal Event by Study Week 27, n (%) Pamidronate (n = 169) Placebo (n = 181) Any SRE 42 (25) 46 (25) Radiation to bone for pain relief 25 (15) 29 (16) Radiation to bone to prevent fracture 8 (5) 7 (4) Nonvertebral fractures 14 (8) 12 (7) Vertebral fractures 11 (7) 10 (6) Spinal cord compression 5 (3) 3 (2) Surgery to bone 5 (3) 6 (3) Hypercalcemia 1 (< 1) 2 (1) Small EJ, et al. J Clin Oncol. 2003;21:

21 ZA vs Placebo: Time to First On-Study SRE Patients Without Event (%) ZA 4 mg ZA 8/4 mg Placebo Patients at Risk, n ZA 4 mg ZA 8/4 mg Placebo Saad F, et al. J Natl Cancer Inst. 2002;94: Days After Start of Study Drug

22 Denosumab vs ZA: Time to First On-Study SRE Proportion of Patients Without SRE Denosumab ZA Median Mos (95% CI) 20.7 ( ) 17.1 ( ) HR: 0.82 (95% CI: ; P =.0002 for noninferiority analysis; P =.008 for superiority analysis) Number of Months Patients at Risk, n Denosumab ZA Fizazi K, et al. Lancet. 2011;377:

23 Time to First and Subsequent On-Study SRE (Multiple Event Analysis)* Cumulative Mean Number of SREs per Patient 2.0 Rate ratio: 0.82 (95% CI: ; 1.8 P =.004; adjusted P =.008) Events, n Denosumab (n = 950) ZA (n = 951) Number of Months *Events occurring at least 21 days apart. Fizazi K, et al. Lancet. 2011;377:

24 (A) Time to first on-study SSE and (B) first and subsequent on-study SSE. M. R. Smith et al. Ann Oncol 2015;26:

25 Comparison of Bone-Directed Therapies Zoledronic Acid Denosumab Route Intravenous Subcutaneous Acute phase reactions Yes No Renal toxicity Yes No Hypocalcemia Rare Not rare ONJ Yes Yes Survival benefit No No Reimbursement concerns Usually not Regional

26 Denosumab: adverse events

27 Osteonecrosis of the jaw

29 Abiraterone and SRE C. Logethetis et al. Lancet Oncol 2012; 13:

30 Cabozantinib

31 Cabozantinib: ORR soft tissue lesions. Phase II data David C. Smith et al. JCO 2013;31: by American Society of Clinical Oncology

32 Bone scan effects of cabozantinib treatment on study patients by American Society of Clinical Oncology David C. Smith et al. JCO 2013;31:

33 Kaplan-Meier estimates of progression-free survival (PFS) in (A) randomly assigned patients with castration-resistant prostate cancer (CRPC) and (B) patients with CRPC by docetaxel pretreatment status. The COMET-1 Phase III trial did not meet its primary endpoint of demonstrating a statistically significant increase in overall survival (OS) for patients treated with cabozantinib as compared to prednisone. The median OS for the cabozantinib arm of the trial was 11.0 months versus 9.8 months for the prednisone arm (hazard ratio 0.90; 95% confidence interval ; p value 0.212) by American Society of Clinical Oncology David C. Smith et al. JCO 2013;31:

Beta emitters: long range increases bone marrow exposure Beta Range in tissue (μm) 50 12 000 Relative particle mass 1 DNA hits for cell kill >1000 Bone

34 Beta emitters: long range increases bone marrow exposure Beta Range in tissue (μm) Relative particle mass 1 DNA hits for cell kill >1000 Bone Marrow Beta emitter Range of beta particle ( cell diameters 2 ) Henriksen G et al. Cancer Res 2002;62:3120 5; Brechbiel M. Dalton Trans 2007;43:

Castrate-resistant prostate cancer: Bone-targeted agents. Pr Karim Fizazi, MD, PhD Institut Gustave Roussy Villejuif, France

Castrate-resistant prostate cancer: Bone-targeted agents Pr Karim Fizazi, MD, PhD Institut Gustave Roussy Villejuif, France Disclosure Participation in advisory boards or as a speaker for: Amgen, Astellas,