Quando e qual o momento de iniciar os Bifosfonatos no Câncer de Próstata

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1 Quando e qual o momento de iniciar os Bifosfonatos no Câncer de Próstata Igor A. Protzner Morbeck, MD, MSc Professor de Medicina Universidade Católica de Brasília Oncologista Clínico Onco-Vida Brasília-DF

2 De acordo com a Resolução 1595/2000 do Conselho Federal de Medicina e RDC 102/2000 da ANVISA, declaro que: 1. Participo de estudos clínicos patrocinados pelas empresas: GSK, Sanofi-Aventis, ImClone, Eli- Lilly 2. Atuo como speaker de eventos das empresas: Pfizer, Sanofi- Aventis, GSK, Novartis, Bayer. 3. Participo como membro do Advisory Board das empresas: Pfizer, GSK, Sanofi-Aventis 4. Não possuo ações de quaisquer destas companhias farmacêuticas.

3 Bone Involvement in Different Tumor Types Disease Prevalence (US) (in Thousands) Incidence of Bone Metastases in Patients With Advanced Disease, % Median Survival of Patients With Bone Metastases, Mos Myeloma 49.6 [1] 84 [2] [4] Lung 327 [1] [3] 8-10 [5] Breast 2051 [1] [3] [6] Prostate 1477 [1] [3] [7] 1. National Cancer Institute. 2. Kyle RA, et al. Mayo Clin Proc. 2003;78: Coleman RE. Oncologist. 2004;9(suppl 4): Palumbo A, et al. Blood. 2004;104: Smith W, et al. Semin Oncol. 2004;31(suppl 4): Lipton A. J Support Oncol. 2004;2: Tu SM, et al. Cancer Treat Res. 2004;118:23-46.

4 Interactions between tumor cells and the bone marrow stroma Roodman GD. Nat Med 2007;13:25-6.

$Patients With Bone Lesions Are at High Risk for Skeletal Complications Patients With SRE (%) 60 50 40 30 20 52 43 Placebo Arms of Large Randomized Studies 25 33 Pathologic fracture Radiation therapy$

5 Patients With Bone Lesions Are at High Risk for Skeletal Complications Patients With SRE (%) Placebo Arms of Large Randomized Studies Pathologic fracture Radiation therapy Surgical intervention Spinal cord compression Breast [1] Prostate [2] Multiple myeloma* [3,4] NSCLC + other 24 mos 24 mos 21 mos solid tumors [5] Cancer Type 21 mos *21-mo data except for surgical intervention and spinal cord compression, for which only 9-mo data are available. 1. Lipton A, et al. Cancer. 2000;88: Saad F, et al. AUA Abstract Berenson JR, et al. J Clin Oncol. 1998;16: Berenson JR, et al. N Engl J Med. 1996;334: Rosen LS, et al. Cancer. 2004;100:

Spinal cord compression Bone marrow compromise

6 Consequences of Prostate Cancer Progression on Bone Metastasis Osteoporosis Osteopenia Worsening bone pain Spinal cord compression Bone marrow compromise Hyper/hypocalcemia Additional therapy such as surgery and radiation

7 Negative Impact of Bone Complications Increased medical costs [1] Treatment of bone complications more than doubles the total treatment costs for patients with bone metastases Impaired mobility [6] Hip fracture associated with a 50% disability rate; 25% of these require nursing home care Skeletal Complications Diminished quality of life [2-4] History of a skeletal complication is associated with lower QoL in breast and prostate cancer Negative impact on survival [5] Men with prostate cancer without skeletal fracture survived 39 mos longer than those with a fracture 1. Groot MT, et al. Eur Urol. 2003;43: Weinfurt KP, et al. Ann Oncol. 2002;13(suppl 5): Weinfurt KP, et al. Med Care. 2004;42: Saad F, et al. Eur Urol. 2004;46: Oefelein MG, et al. J Urol. 2002;168: Riggs BL, et al. Bone. 1995;17:505S-511S.

8 Spectrum of Bone Disease in Prostate Cancer Prevention of Skeletal Related Events Castrate sensitive, nonmetastatic Castrate resistant, nonmetastatic Castrate resistant, metastatic

9 Bisphosphonate

10 IV Bisphosphonates (e.g. Zoledronate) Treatment of osteoporosis (accelerated by ADT use) Treatment of hypercalcemia Prevention of fractures and SREs Pain relief for bone metastases Improved quality of life Antitumor effects (?) 1. Doggrell SA. Expert Rev Anticancer Ther. 2009;9: Winter MC, et al. Curr Opin Oncol. 2009;21:

11 Zoledronic Acid in Hormone-Refractory Prostate Cancer Eligibility Criteria Patients with prostate cancer Hormone refractory Bone metastases (N = 643) Zoledronic acid 4 mg q3w (n = 214) Zoledronic acid 4 mg q3w (initially 8 mg) (n = 221) Placebo q3w (n = 208) Patients on the 8-mg arm reduced to 4 mg because of renal toxicity Primary outcome: proportion of patients having 1 SRE Secondary outcomes: time to first on-study SRE; proportion of patients with SREs, and TTP Saad F, et al. J Natl Cancer Inst. 2002;94:

12 Zoledronic Acid vs Placebo: Time to First On-Study SRE Patients Without Event (%) Patients at Risk, n Zol acid 4 mg Zol acid 8/4 mg Placebo Zoledronic acid 4 mg Zoledronic acid 8/4 mg Placebo Days After the Start of Study Drug Saad F, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002;94: , by permission of Oxford University Press.

13 Cumulative Incidence of SREs 100 Placebo P =.001 Skeletal-Related Events Radiation to bone Events/100 Patients 50 0 Zoledronic acid Months Pathologic fracture Spinal cord compression Surgery to bone Change in cancer therapy Saad F, et al. J Natl Cancer Inst. 2002;94:

14 ASCO 2011, Meulenbeld HJ, #4518 Randomized phase III study of docetaxel with or without Risedronate in patients with bone metastases from castration-resistant prostate cancer (CRPC): The Netherlands Prostate Study. Randomized trial in men with CRPC & bone mets (n=592) Docetaxel vs. docetaxel + risedronate (oral, daily) Similar PSA responses and pain responses No PFS advantage No OS benefit

15 Denosumab: Mechanism of Action RANKL RANK Denosumab RANK-expressing tumor cells Cytokines and growth factors (IL-6, IL-8, IL-1ß, PGE 2, TNF-α, CSF-1, PTHrP) Direct effects on tumor? Growth factors (TGF-ß, IGFs, FGFs, PDGFs, BMPs) Bone resorption Ca 2+ Roodman GD. N Engl J Med. 2004;350:

16 Denosumab vs Zoledronic Acid to Prevent SREs Prospective, double-blind, placebo-controlled phase III trial Patients with CRPC and bone metastases, no current or previous IV treatment with bisphosphonate (N = 1901) Denosumab 120 mg SC + Placebo IV q4w (n = 950) Zoledronic Acid 4 mg IV + Placebo SC q4w (n = 951) Primary endpoint SREs: fracture, radiation or surgery to bone, spinal cord compression Fizazi K, et al. Lancet. 2011;377:

17 Denosumab vs Zoledronic Acid: Time to First On-Study SRE 1.00 Denosumab Zoledronic acid Median Mos (95% CI) 20.7 ( ) 17.1 ( ) Proportion of Patients Without an SRE Patients at Risk, n Denosumab Zoledronic acid HR: 0.82 (95% CI: ; P =.0002 for noninferiority analysis; P =.008 for superiority analysis) Study Mo

18 Adverse Events of Interest Subject Incidence, n (%) Zoledronic Acid (n = 945) Denosumab (n = 943) Infectious adverse events 375 (39.7) 402 (42.6) Infectious serious adverse events 108 (11.4) 130 (13.8) Acute-phase reactions (first 3 days) 168 (17.8) 79 (8.4) Renal adverse events* 153 (16.2) 139 (14.7) Cumulative rate of ONJ 12 (1.3) 22 (2.3) Yr 1 5 (0.5) 10 (1.1) Yr 2 8 (0.8) 22 (2.3) Hypocalcemia 55 (5.8) 121 (12.8) New primary malignancy 10 (1.1) 18 (1.9) *Includes renal failure, increased blood creatinine, acute renal failure, renal impairment, increased blood urea, chronic renal failure, oliguria, hypercreatinemia, anuria, azotemia, decreased creatinine renal clearance, decreased urine output, abnormal blood creatinine, proteinuria, decreased glomerular filtration rate, and nephritis. P =.09. Fizazi K, et al. ASCO Abstract LBA4507. Fizazi K, et al. Lancet. 2011;377:

19 Denosumab: Integrated Analysis Prostate Cancer n = 1,901 Breast Cancer n = 2,046 Solid Tumors + Myeloma n = 1,776 Integrated Analysis N = 5,723 Risk reduction for 1 st SRE vs. zoledronate HR % CI ( ) P = [superiority] HR % CI ( ) P = [superiority] HR % CI ( ) P = [non-inferiority] HR % CI ( ) P < [superiority] Risk reduction for 1 st and subsequent SRE vs. zoledronate HR % CI ( ) P = [superiority] HR % CI ( ) P = [superiority] HR % CI ( ) P = [non-inferiority] HR % CI ( ) P < [superiority] Lipton A, et al. ESMO 2010 (abstract 1249P).

20 Spectrum of Bone Disease in Prostate Treatment-Related Fractures Cancer Castrate sensitive, nonmetastatic Castrate resistant, nonmetastatic Castrate resistant, metastatic

21 Proportion of Patients With Fractures 1-5 Yrs After Cancer Diagnosis +6.8%; P < ADT (n = 6650) No ADT (n = 20,035) 15 Frequency (%) Any Fracture +2.8%; P < Fracture Resulting in Hospitalization Shahinian VB, et al. N Engl J Med. 2005;352:

22 GnRH Agonists Decrease BMD in Men With Prostate Cancer 2 Percent Change Lumbar Spine Total Hip Control GnRH agonist P <.001 for each comparison 12-mo data Mittan D, et al. J Clin Endocrinol Metab. 2002; 87:

23 Alendronate Increases BMD During GnRH Agonist Therapy BMD Percent Change Placebo Alendronate P <.005 for each comparison 12-mo data -3 Lumbar Spine Total Hip Greenspan SL, et al. Ann Intern Med. 2007;146: JCO September 20, 2008 vol. 26 no

24 Denosumab Fracture Prevention Study Current androgen deprivation therapy for patients with prostate cancer who are older than 70 yrs of age or with T score < -1.0 Denosumab 60 mg q6m for 3 yrs Placebo q6m for 3 yrs (N = 1468) Primary endpoints: BMD, new vertebral fractures Smith MR. N Engl J Med. 2009;361:

25 Denosumab to Increase BMD in Patients With Prostate Cancer Receiving ADT Lumbar Spine Percent Change in BMD From Baseline Denosumab Difference at 24 mos: 6.7 percentage points Mos Placebo Total Hip Percent Change in BMD From Baseline Difference at 24 mos: 4.8 percentage points Mos Smith MR. N Engl J Med. 2009;361:

26 Denosumab to Prevent Fractures New Vertebral Fracture (%) Patients, n P =.004 P =.004 P = Mos Denosumab Placebo Smith MR. N Engl J Med. 2009;361:

27 Spectrum of Bone Disease in Prostate Cancer Prevention of Bone Metastasis? Castrate sensitive, nonmetastatic Castrate resistant, nonmetastatic Castrate resistant, metastatic

28 Lancet Jan;379(9810):39-46 Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebocontrolled trial Increased bone-metastasis-free survival by a median of 4 2 months compared with placebo (median 29 vs 25 2 months; HR 0 85, p=0 028). Denosumab also significantly delayed time to first bone metastasis (33 2 vs 29 5 months; HR 0 84, p=0 032).

29 Clinical Case 68-yr-old male presents with mild bone pain after neglecting to see a physician for more than 15 yrs PSA is found to be 328, and bone scan reveals diffuse bone metastases. Normal calcium. Prostate needle biopsy confirms Gleason 4+4 Adenocarcinoma of the prostate Patient is started on Bicalutamide followed 1 wk later by Gosereline

30 Would you recommend bone-targeted therapy for this patient? A.No B.Yes, denosumab 120 mg q4 wks C.Yes, pamidronate 90 mg q3-4 wks D.Yes, zoledronic acid 4 mg q3-4 wks E.Unsure

31 Would you recommend bone-targeted therapy for this patient? No X Yes, denosumab 120 mg q4 wks X Yes, pamidronate 90 mg q3-4 wks X Yes, zoledronic acid 4 mg q3-4 wks Maybe. Unsure

32 CALGB 90202: Zoledronate in Preventing Skeletal (Bone)- Related Events in Patients Who Are Receiving Androgen Deprivation Therapy For Prostate Cancer and Bone Metastases Randomize PD ADT + placebo q4 wk Zoledronic acid q3 wk Goal N = 680; over 2/3 accrued ADT + zoledronic acid q4 wk Zoledronic acid q3 wk Double blinded Open label Primary endpoint: time to SRE; secondary endpoints: OS, toxicity ClinicalTrials.gov. NCT

33 Take Home Points Disease-related skeletal complications are common in men with metastatic prostate cancer Bone health is of critical importance for men with advanced prostate cancer Zoledronic acid decreases risk of SREs in men with castrate-resistant disease and bone metastases Denosumab is superior to zoledronic acid for delay in first SREs and rate of SREs in this setting Denosumab increased bone-metastasis-free survival. New perspective?

34 Obrigado pela atenção!

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,