Presentation on theme: "Más es posible: CPRC con Metástasis Óseas Sintomáticas Javier Puente, MD, PhD Hospital Universitario Clinico San Carlos Medical Oncology Department Complutense."— Presentation transcript:
Más es posible: CPRC con Metástasis Óseas Sintomáticas Javier Puente, MD, PhD Hospital Universitario Clinico San Carlos Medical Oncology Department Complutense University Associate Professor of Medicine
Prostate Cancer Disease Landscape: N=230,000 in USA (some speculation…) Patients at Diagnosis Metastatic CRPC N=30,000 in USA ADT Newly diagnosed Progression Non – Metastatic Prostate Cancer Intermittent ADT and develop mets on Rx break with normal testo 95% of 230,000 ~ 220,000 ~75% no relapse 5% of 230,000 ~ 10,000 5% relapse post local Rx & mets* ~10,000 ~20,000 M1 HSPC prior to CRPC ~10,000 M0 CRPC prior to mCRPC (25% BCR) *either relapse with mets or Observe rising PSA and mets
Bone metastases: very common in prostate cancer INCIDENCE OF BONE METASTASES Petrylak 4 (SWOG 99-16) Tannock 3 (TAX 327) Scher 2 (AFFIRM) de Bono 1 (COU-AA-301) 89-90% 91-92% 90-92% 84-88% AFFIRM, A Study Evaluating the Efficacy and Safety of the Investigational Drug MDV3100; CRPC, castration-resistant prostate cancer; SWOG, Southwest Oncology Group. 1. de Bono J, et al. N Engl J Med. 2011;364:1995–2005. 2. Scher H, et al. N Engl J Med. 2012;367:1187–1197. [supplemental appendix] 3. Tannock I, et al. N Engl J Med. 2004;351:1502–1512. 4. Petrylak D, et al. N Engl J Med. 2004;351:1513–1520.
Hormonal signals impact bone structure Boiley WJ, et al. Nature 2003
The “vicious cycle” of bone metastases Gatrell B & Saad F, Nat Rev Clin Oncol 2014
Osteoclast differentiation and activation Boiley WJ, et al. Nature 2003
Discovery of the RANK signalling pathway Boiley WJ, et al. Nature 2003
“Traditional” drug development strategies have failed microenvironment targeting drugs Antonarakis ES, J Clin Oncol 2013
Inhibitors of osteoclast/osteoblast function reduce SREs but do not prolong survival Saad F, et al. Nat Rev Clin Oncol 2014
Phase III trial of denosumab in bone metastases from CRPC Fizazi K, et al. Lancet 2011; 377(9768): 813-22
Denosumab: Time to first SRE Fizazi K, et al. Lancet 2011; 377(9768): 813-22
Can the bone tropism of PC be turned into an Achilles Heel? Prostate Cancer is the MOST BONE TROPIC of the major solid tumors Bone/Soft tissue ratios are exceptionally high for metastatic prostate cancer compared to other solid tumors More than 90% of metastatic prostate cancer patients enrolled in recent mCRPC trials have evidence of bony spread. Can we exploit bone tropism for therapeutic benefit?
Proposed Spiral Model for Pca progression Logothetis et al. Cancer Discov 2013
Bone stromal targeted therapy: many attempts and few successes! Bone stromal-targeted radioharmaceutical Strontium-89, samarium-153, radium-223 Bone stromal + tumor targeting with endothelin antagonism ZD4054 and atrasentan Bone stromal + tumor targeting with p60src inhibition Dasatinib Bone stromal tumor targeting via antiRANK ligand inhibition AntiRANK ligand monoclonal (denosumab) Bone stroma targeting with biphosphonates Clodronate and zoledronic acid
Radium-223 is a targeted alpha emitter that selectively binds to areas of increased bone turnover in bone metastases and emits high-energy alpha particles of a short range (<100 μm) 1 As a bone-seeking calcium mimetic, it is bound into newly formed bone stroma, especially within the microenvironment of osteoblastic or sclerotic metastases 2,3 The high-energy alpha particle radiation induces mainly double-stranded DNA breaks that result in a potent and highly localized cytotoxic effect in target areas 2,4-6 The short path of the alpha particles also means that the toxic effects on adjacent healthy tissue and particularly the bone marrow may be minimized 3,7-8 Overview: Radium-223 MOA 1. Bruland OS, et al. Clin Cancer Res. 2006;12:6250s–7s. 2. Henriksen G, et al. Cancer Res. 2002;62:3120–3125. 3. Henriksen G, et al. J Nuc Med. 2003;44:252–59. 4. Lewington VJ. J Nucl Med. 2005;46(suppl):38S–47S. 5. Liepe K. Curr Opin Investig Drugs. 2009;10:1346–58. 6. McDevitt MR, et al. Eur J Nucl Med. 1998;25:1341–51. 7. Kerr C. Lancet Oncol. 2002;3:453. 8. Li Y, et al. Expert Rev Anticancer Ther. 2004;4:459–68.
ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) phase III study design ALSYMPCA was halted early after the positive efficacy results reported from a planned interim analysis of 809 patients with 314 deaths occurred. An updated analysis of efficacy and safety was performed from all 921 enrolled patients when 528 deaths had occurred. Parker C, et al. N Engl J Med. 2013;369(3):213–223.
Histologically confirmed, progressive CRPC a with ≥2 bone metastases (on skeletal scintigraphy) and no known visceral metastases Patients were receiving best standard of care Patients had either received docetaxel, were not fit enough or willing to receive docetaxel, or did not have docetaxel available Symptomatic disease, defined as regular use of analgesic medication for cancer-related bone pain or treatment with EBRT for bone pain within previous 12 weeks PSA ≥5 ng/mL with evidence of progressively rising PSA values b ECOG PS score of 0 to 2 c Life expectancy of ≥6 months Adequate hematologic, renal, and liver function 18 CRPC, castration-resistant prostate cancer; EBRT, external beam radiation therapy; ECOG PS, Eastern Cooperative Oncology Group Performance Status; PSA, prostate-specific antigen. a.Castration-resistant disease was defined as serum testosterone ≤50 ng/dL (≤1.7 nmol/L) after bilateral orchiectomy or during maintenance on androgen-ablation therapy with luteinizing hormone-releasing hormone agonist or polyestradiol phosphate throughout the study. b.Two consecutive increases over previous reference value. c.Score 0 denotes a patient fully active with no functional restriction, and increasing numbers denote greater functional compromise. ALSYMPCA: Inclusion Criteria
ALSYMPCA: patient demographics and baseline characteristics (ITT population) Parker C, et al. N Engl J Med. 2013;369(3):213–223.
The updated analysis confirmed the 30% reduction in risk of death (HR=0.70) for patients in the radium-223 group compared with placebo. ALSYMPCA Updated Analysis: Radium-223 Significantly Improved OS ━ Radium-223 6145785043692741781056041187100 ━ Placebo 3072882281571036739241474210 20 0 40 60 80 100 Survival, % Months Since Randomization 091524303936332721181263 Increase OS ∆=3.6 mos MEDIAN OS (months) ━ Radium-223:14.9 ━ Placebo:11.3 HR (95% CI): 0.70 (0.58–0.83) P <0.001 Parker C, et al. N Engl J Med. 2013;369(3):213–223.
ALSYMPCA Updated Analysis: Radium-223 Improved OS Across All Patient Subgroups 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 OURCE: Parker C, et al. N Engl J Med. 2013;369(3):213–223. 0.52.01.0 Parker C, et al. N Engl J Med. 2013;369(3):213–223.
The significant improvement in all main secondary efficacy endpoints provided support for the benefit of radium-223 (+ BSoC) over placebo (+ BSoC). ALSYMPCA Updated Analysis: Radium-223 Significantly Improved All Secondary Efficacy Endpoints ALP, alkaline phosphatase; BSoC, best standard of care; CI, confidence interval; ITT, intention-to-treat; PSA prostate-specific antigen; SSE, symptomatic skeletal event. a.Number of patients without missing values. b..In patients who had elevated total ALP at baseline.. Parker C, et al. N Engl J Med. 2013;369(3):213–223.
ALSYMPCA Updated Analysis: Safety Profiles Were Similar Between 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. Parker C, et al. N Engl J Med. 2013;369(3):213–223.
The significant survival benefit observed with radium-223, regardless of prior docetaxel use, is consistent with that reported n the ALSYMPCA ITT population (radium-223 14.9 vs 11.3 months with placebo (HR=0.695; 95% CI, 0.581-0.832; P=0.00007). Overall Survival was Significantly Improved with Radium-223, Regardless of Prior Docetaxel Use Vogelzang NJ, et al. J Clin Oncol. 31, 2013 (suppl; abstr 5068). ━ Ra-223 262236168118703113710 ━ PBO 133113744224149310 ━ Ra-223 3523272381558845275100 ━ PBO 17415210461351554110 MEDIAN OS, NO PRIOR DTX (months) ━ Radium-223 (n=262):16.1 ━ Placebo (n=133):11.5 HR (95% CI): 0.75 (0.56–0.99) P =0.039 20 0 40 60 80 100 Patients, % 01220323628241684 Months MEDIAN OS, PRIOR DTX (months) ━ Radium-223 (n=352):14.4 ━ Placebo (n=174):11.3 HR (95% CI): 0.71 (0.57–0.89) P =0.003 20 0 40 60 80 100 Patients, % 0122032403628241684 Months
Safety of cytotoxic chemotherapy following Radium-223 Sartor O, et al. Ann Oncol 2012 (suppl; abstr 936P). Overall Survival in the ITT Population In the updated ALSYMPCA analysis of all 921 randomized patients prior to placebo crossover, radium-223, compared with placebo, significantly improved OS in patients with CRPC and bone metastases (P=0.00007; HR=0.695; 95% CI, 0.581-0.832) −Median OS was 14.9 months in the radium-223 group vs 11.3 months in the placebo group
20 0 40 60 80 100 Patients Without SSE, % Months Since Randomization 091524302721181263 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 61449634219912963318810 ━ Placebo 30721111756362097410 ALSYMPCA Updated Analysis: Radium-223 Significantly Improved Time to SSE Increase TTSSE ∆=5.8 mos Parker C, et al. N Engl J Med. 2013;369(3):213–223.
Radium-223 Reduced the Overall Risk of SSEs Regardless of Baseline Stratification Factors: Bisphosphonate Use at Study Entry (Yes/No) ━ Radium-223 ━ Placebo 36424712005123068 18310341014919 0 0 CI, confidence interval. HR, hazard ratio. SSE, symptomatic skeletal event. NOTE: ALSYMPCA was not powered to detect differences between subgroups; P values are for descriptive purpose only and are not adjusted for multiplicity. Very few placebo patients were still evaluable at later time points on the curve; the hazard ratio is the best interpretation of radium-223 effect over the complete observed time frame.. MEDIAN TIME TO FIRST SSE (months) ━ Radium-223 (n=364):11.8 ━ Placebo (n=183):8.4 HR (95% CI): 0.77 (0.58–1.02) P =0.07 20 0 40 60 80 100 Patients Without Symptomatic Skeletal Events, % 03224168 20 0 40 60 80 100 Patients Without Symptomatic Skeletal Events, % 03224816 MEDIAN TIME TO FIRST SSE (months) ━ Radium-223 (n=250):19.6 ━ Placebo (n=124):10.2 HR (95% CI): 0.49 (0.33–0.74) P =0.00048 4122028 Month BISPHOSPHONATE USE AT STUDY ENTRYNO BISPHOSPHONATE USE AT STUDY ENTRY 2820124 Treatment Period ━ Radium-223 ━ Placebo 2501931150182561 12471290131017 3 3 Parker C, et al. N Engl J Med. 2013;369(3):213–223.
There was a trend showing improvement in OS with radium-223 treatment compared with placebo in each tALP tertile* Exploratory Post Hoc Analysis of Overall Survival by Tertiles of Baseline tALP in the Radium-223 and Placebo Cohorts *tALP ranges in the tertiles are slightly different between radium-223 and placebo cohorts. Heinrich D, et al. Presented at the 29 th Annual EAU Congress. Stockholm, Sweden. (Abstract 865). RADIUM-223 MEDIAN OS [months (95%CI)] ━ Tertile 1 (N=205):23.9 (17.5-33.8) tALP min-max:32-131 ━ Tertile 2 (N=207):14.1 (12.0-15.9) tALP min-max:132-333 ━ Tertile 3 (N=202):10.2 (9.1-11.7) tALP min-max:334-6431 20 0 Percentage of Patients 80 100 40 60 Months 010302040 PLACEBO MEDIAN OS [months (95%CI)] ━ Tertile 1 (N=102):18.8 (13.9-24.5) tALP min-max:29-153 ━ Tertile 2 (N=104):11.5 (9.3-13.5) tALP min-max:154-353 ━ Tertile 3 (N=101):7.5 (6.5-9.1) tALP min-max:360-4805 20 0 Percentage of Patients 80 100 40 60 Months 010302040
Radium-223 patients with a confirmed tALP decline at week 12 had a significantly longer median OS versus radium-223 patients with no confirmed tALP decline (median OS: 17.8 months vs 10.4 months; HR=0.45; 95% CI, 0.34-0.61; P <0.0001 ). 29 Radium-223 Patients with a Confirmed tALP Decline at Week 12 Had Significantly Longer Overall Survival *Confirmed tALP decline was defined as any decrease from baseline at week 12, confirmed ≥3 weeks later. Sartor O, et al. J Clin Oncol. 31, 2013 (suppl; abstr 5080). 20 0 40 60 80 100 Patients, % Months 0324024168 MEDIAN OS (months) ━ Confirmed tALP decline (n=400):17.8 ━ No confirmed tALP decline (n=97):10.4 HR (95% CI): 0.45 (0.34-0.61) P <0.0001
Daniel Petrylak at 2014 ASCO Annual Meeting Sequencing CRPC therapy-2010 Metastatic, minimally symptomatic CRPC Symptomatic or poor- prognosis CRPC Progresssion after docetaxel chemotherapy Secondary hormonal Rx Docetaxel Mitoxantrone BSC Survival benefit Not Known3 months Not Known Zoledronic acid with CRPC (M1 ddisease)
Daniel Petrylak at 2014 ASCO Annual Meeting Sequencing CRPC therapy-2015 Metastatic, minimally symptomatic CRPC Symptomatic or poor- prognosis CRPC Progresssion after docetaxel chemotherapy Secondary hormonal Rx Docetaxel Mitoxantrone BSC Survival benefit Not Known3 months Not Known Denosumab or Zoledronic acid with CRPC (M1 ddisease) 2010 2015 Survival benefit Sipuleucel-T (4 m) Abiraterone (5.2 m) Enzalutamide (NA) Docetaxel Abiraterone (4 m) Cabazitaxel (2.5 m) Enzalutamide (4.8 m) 3 months Radium 223 (3.6 m)
Disease-modifying agents and skeletal outcomes Gatrell B & Saad F, Nat Rev Clin Oncol 2014
A randomized, open-label phase 2a study evaluating quantified bone scan response following treatment with radium-223 dichloride alone or in combination with abiraterone acetate or enzalutamide in CRPC patients with bone metastases Phase 2a Study Evaluating Quantified Bone Scan Response After Treatment With Ra-223 Alone or in Combination With Abiraterone Acetate or Enzalutamide in CRPC Patients with Bone Metastases SSE-FS, symptomatic skeletal event–free survival. SSE-FS will be calculated from time of randomization to date of first SSE or death. *SSEs include time to EBRT use for bone pain or occurrence of new pathologic fracture (vertebral and non-vertebral), spinal cord compression, or tumor-related orthopedic surgery. Petrylak D, et al. J Clin Oncol. 32:5s, 2014 (suppl; abstr TPS5103). ASSESSMENTS: Imaging assessments will be done at screening and at weeks 8, 16, and 24, then every 12 weeks for 2 years following the last radium-223 dose or until progression. ENROLMENT: This US-based study with 20 planned sites is currently recruiting patients. As of May 16, 4 patients have been recruited, 3 have been enrolled; first patient first visit occurred on March 7, 2014. PATIENTS (N=66) Histologically or cytologically confirmed adenocarcinoma of the prostate Known castration-resistant disease Serum PSA ≥ 2 ng/mL (μg/L) ≥2 bone metastases on bone scan assessed within 12 weeks prior to randomization ECOG PS 0 to 2 Visceral and CNS metastases excluded. R R 1:1:1 Radium-223 50 kBq/kg IV every 4 wk × 6 Radium-223 50 kBq/kg IV every 4 wk × 6 + abiraterone 1000 mg qd PO and prednisone 5 mg bid × 2 yrs following last radium-223 dose Radium-223 50 kBq/kg IV every 4 wk × 6 + enzalutamide 160 mg qd PO × 2 yrs following last radium-223 dose PRIMARY OBJECTIVE Test bone scan response at week 24 based on quantified BSLA for each regimen SECONDARY OBJECTIVES Safety, rPFS, SSE-FS*, OS, and time to radiologic bone progression.
ERA 223: A Phase III Trial of Ra-223 Plus Abiraterone Acetate and Prednisone in the Treatment of Asymptomatic or Mildly Symptomatic Chemotherapy-Naïve Patients With Bone-Predominant mCRPC *SSE-FS defined as the time from randomization to occurrence of on-study SSE (defined as EBRT for skeletal symptoms, new symptomatic pathologic non-vertebral bone fracture, spinal cord compression, tumor-related orthopedic surgical intervention), or death from any cause. **Time to first on-study SSE, ALP progression, PSA progression; percentage change in total ALP from baseline; time to increase in physical symptoms based on the FACT Prostate Symptom Index: Disease-Related Subscale—Physical (FPSI-DRS-P) score. Smith MR, et al.. Ann Oncol. 2014;25 (Suppl 4): iv1 - mdu438.66. abstr 803TiP. This international, randomized, double-blind, placebo-controlled, phase III study (ERA 223, NCT02043678) is being conducted in North America, Europe, Asia, Australia, Brazil, and Israel at 168 investigative sites. ENROLMENT: This study is currently recruiting patients. As of September 5, 2014, 74 patients have been screened, 43 have been enrolled. ANALYSIS: 800 patients expected to provide 389 SSE-FS events are needed to detect a 39% increase in SSE-FS; i.e., an overall 0.05 level 2-sided log-rank test has approximately 90% power to detect a difference between the 2 SSE-FS curves if the alternative hypothesis HR is 0.72, assuming the median SSE-FS is 29.2 months for radium ‑ 223 versus 21.0 months for control. PATIENTS (N=800) Chemo-naïve bone metastatic CRPC Asymptomatic or mildly symptomatic >2 bone metastases No known brain or visceral metastasis ECOG PS 0 or 1 STRATIFICATION Geography (EU, NA, AUS vs Asia vs ROW Concurrent use of bisphosphonates or denosumab alone Total ALP 90 U/L R R 1:1 Radium-223 50 kBq/kg IV every 4 wk × 6 + abiraterone (100 mg once daily) and prednisone/prednisolone (5 mg BID) Matching placebo every 4 wk × 6 + abiraterone (100 mg once daily) and prednisone/prednisolone (5 mg BID) PRIMARY OBJECTIVE SSE-free survival (SSE-FS)* SECONDARY OBJECTIVES OS, time to opiate use for cancer pain, pain progression, cytotoxic chemotherapy, rPFS safety EXPLORATORY OBJECTIVES**
Modeling Clinical Prostate Cancer Wan X, et al. Sci Trans Med 2014
FGFR1: Cross-species analysis PC BM Wan X, et al. Sci Trans Med 2014
Conclusions I mCPRC is associated with complications in bone known as skeletal-related events (SREs) that are associated with decreases QoL and increased mortality. Osteoclas-targeted agents including the bisphosphonate zoledronic acid and the monoclonal antibody denosumab are used to reduce incidence of SREs and to decrease loss of BMD. Recently approved agents included pathway inhibitors abiraterone, enzalutamide and radium-223 have been shown to increase survival and to decrease skeletal morbidity in mCPRC.
Conclusions II ALSYMPCA conclusions: In CRPC patients with bone metastases: Only one compound, radium-223 significantly prolongs overall survival P value=0.00185; HR=0.695; 95% IC: 0.552-0.875 Radium-223 significantly prolonged time to first clinically relevant SRE P value=0.00046; HR=0.610; 95%IC: 0.461-0.807 Radium-223 was very well tolerated
THANK YOU Javier Puente, MD, PhD Hospital Universitario Clinico San Carlos Medical Oncology Department Complutense University Associate Professor of Medicine