ACTUALIZACIONES EN TRATAMIENTOS DIRIGIDOS AL HUESO. COMBINACIÓN CON OTRAS ESTRATEGIAS TERAPÉUTICAS. ÁLVARO PINTO Servicio de Oncología Médica Hospital Universitario La Paz IdiPAZ, Madrid
INTRODUCTION High prevalence of bone metastases in the setting of mcrpc Associated with morbidity and mortality Skeletal related events (SREs) - Spinal cord compression (SCC) - Pathologic fracture - Need for surgery - Palliative radiotherapy Influence in survival and quality of life Economic burden 5 10% lymph node only ~20% bone visceral disease < 5% visceral only ~70 % bone lymph nodes
INTRODUCTION Patients With SRE, % Any Pathologic fracture Radiation therapy Surgical intervention Spinal cord compression 24 months Saad F, et al. JNCI. 2002;94(19):1458-1468; Saad F, et al. Eur Urol Suppl. 2007;6(11):683-688.
INTRODUCTION Probability 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 No SRE (n = 355) 1 SRE (n = 116) 0 90 180 270 360 Survival, days 360 Days Survival No SRE: 49.7% 1 SRE: 28.2% P =.02 Median Survival Times No SRE: 338 days (95% CI = 189, 460) 1 SRE: 248 days (95% CI = 181, 296) SREs Are Associated With Lower Survival in Prostate Cancer DePuy V, et al. Support Care Cancer. 2007;15:869-876.
INTRODUCTION Total Physical Functional Emotional Change/Standard Deviation a a a a a a Change in FACT-G score for patients with an event vs patients without an event a P <.05. Weinfurt et al. Ann Oncol. 2005;16(4):579-584.
INTRODUCTION Median average cost: 21.000$ Inpatient SREs: 54.700$ Outpatient SREs: 11.700$ Hospital stay: range 1-65 days SCC: 11.5 days Radiaton to bone: 2.370 Surgery to bone: 4.260 Pathologic fracture: 4.710 SCC: 7.900 Average hospital length of stay: 21.6 days (75% of all costs) Yong et al. Curr Opin Oncol 2014;26:274-83; Durán et al. Clin Transl Oncol 2014;16:322-9.
BONE TARGETED THERAPY DOES IT MAKE SENSE?
Deng et al. Cancer Treat Rev 2014;40:730-8
DENOSUMAB
DENOSUMAB Key Inclusion Criteria Castration-resistant prostate cancer and 1 bone metastases Key Exclusion Criteria Current or prior IV bisphosphonate treatment R A N D O M I Z A T I O N Denosumab 120 mg SC and Placebo IV* every 4 weeks (n=950) Zoledronic Acid 4 mg IV* and Placebo SC every 4 weeks (n=951) E N D O F S T U D Y Recommended: Daily supplementation with calcium ( 500 mg) and vitamin D ( 400 U) Primary Endpoint: Time to first on-study skeletal-related event (SRE) (Non-inferiority) Secondary : Time to first on-study SRE (Superiority), time to first and subsequent on-study SRE(s) (Superiority) Fizazi et al. Lancet 2011;377:813-22
DENOSUMAB Fizazi et al. Lancet 2011;377:813-22
DENOSUMAB Fizazi et al. Lancet 2011;377:813-22
DENOSUMAB ADVERSE EVENTS Fizazi et al. Lancet 2011;377:813-22
DENOSUMAB - HYPOCALCEMIA CONDITION RECOMMENDED STRATEGY Pre existing hypocalcemia Treat before initiating therapy Start of treatment Together with at least 500 mg of calcium and 400 UI of vitamin D daily Severe renal failure (creatinine clearance < 30 ml/min) or undergoing dialysis Monitor calcium levels Hypocalcemia during therapy Consider additional calcium supplementation
DENOSUMAB SEVERE RENAL FAILURE (ESMO 2014) S C R E E N I N G Informed consent Screening assessments Begin/adjust calcium and vitamin D supplementation (stage 4 CKD patients) Stage 4 CKD (CrCl <30 ml/min) (n=15) Denosumab 120 mg SC Stage 5D CKD, requiring hemodialysis (n=15) Denosumab 120 mg SC Dose 1 Dose 2 E N D O F S T U D Y Clinically significant adverse events or laboratory abnormalities were followed until resolution/considered stable Days -21 to Day -1 Day 1 Day 29 Day 112 Day 113 PRIMARY OBJECTIVE: Incidence of clinically significant hypocalcemia Block et al. ESMO 2014: abstract 1512P and poster presentation.
DENOSUMAB SEVERE RENAL FAILURE (ESMO 2014) CKD Patients, n (%) Stage 4 (n=16) Stage 5D (n=16) All (n=32) Albumin adjusted serum calcium <7.0 mg/dl * 0 (0.0) 1 (6.3) 1 (3.1) Symptomatic hypocalcemia 1 (6.3) 1 (6.3) 2 (6.3) Total: clinically significant hypocalcemia 1 (6.3) 2 (12.5) 3 (9.4) *CTCAE grade 3 or greater hypocalcemia (<7.0 mg/dl [1.75 mmol/l]); Defined as both a clinical adverse event of hypocalcemia and a concomitant symptom of hypocalcemia (e.g., hypoesthesia, paresthesia, muscle cramps, seizure, prolonged QT interval) that occurred along with the hypocalcemia event or decreased serum calcium levels; Defined as albumin adjusted calcium <7.0 mg/dl (1.75 mmol/l) or symptomatic hypocalcemia Block et al. ESMO 2014: abstract 1512P and poster presentation.
DENOSUMAB OSTEONECROSIS OF THE JAW Prostate cancer Overall ONJ events* 0 12 Months Pt years Pts at beginning of time period, n Pts with ONJ events, n (rate) > 12 Months Pt years Pts at beginning of time period, n Pts with ONJ events, n (rate) Total Pt years Pts at beginning of time period, n Pts with ONJ events, n (rate) ZA (n = 945) 704.7 945 5 (0.7) 343.6 441 7 (2.0) 1048.3 945 13 (1.2) Dmab (n = 943) 721.9 943 10 (1.4) 383.0 494 13 (3.4) 1105.0 943 23 (2.1) ZA (n = 2836) 2112.8 2836 16 (0.8) 1205.2 1447 27 (2.2) 3318.0 2836 44 (1.3) Dmab (n = 2841) 2145.6 2841 22 (1.0) 1228.8 1494 41 (3.3) 3374.4 2841 63 (1.9) P value 0.3711 0.1063 0.0848 Lipton et al. ASCO 2013 [abstract #9640]
DENOSUMAB PAIN CONTROL
OSTEOCLAST-TARGETED AGENTS Gartrell et al. Nat Rev Clin Oncol 2014;11:335-45
DENOSUMAB - CONCLUSIONS Active agent to prevent delay the onset of SREs Superiority over zoledronic acid No impact on survival Advantages over zoledronic acid: Subcutaneous administration No need of normal renal function Watch out for osteonecrosis of the jaw and hypocalcemia
RADIUM-223 Alkaline earth metal Bone seeker (calcium mimic) α-emitter, 28 MeV t ½ = 11.4 days High linear energy transfer Track length < 100 μm 2 10 cell diameter impact Strong cell killing effect 20 Ca Sr 38 56 Ba Ra 88 McDevitt MR, et al. Eur J Nucl Med. 1998;25(9):1341-51 21
RADIUM-223 α β γ α radiation consists of helium ( 4 He) nuclei and is stopped by a sheet of paper or skin β radiation, consisting of electrons, is halted by an aluminum plate or plastic Paper Aluminum Lead or concrete Water or polyethylene γ radiation, consisting of energetic photons, is attenuated by dense material
RADIUM-223 ALSYMPCA TRIAL TREATMENT PATIENTS Confirmed symptomatic CRPC 2 bone metastases No known visceral metastases Postdocetaxel or unfit for docetaxel STRATIFICATION Total ALP: < 220 U/L vs 220 U/L Bisphosphonate use: Yes vs No Prior docetaxel: Yes vs No R A N D O M I S E D 2:1 N = 922 6 injections at 4-week intervals Radium-223 (50 kbq/kg) + Best standard of care Placebo (saline) + Best standard of care PRIMARY ENDPOINT: OVERALL SURVIVAL
RADIUM-223 Patients With Adverse Events (AEs), n (%) Radium-223 (n = 509) Placebo (n = 253) All grade AEs 450 (88) 237 (94) Grade 3 or 4 AEs 257 (51) 150 (59) Serious AEs (SAEs) 220 (43) 139 (55) Discontinuation due to AEs 68 (13) 51 (20) Parker et al. NEJM 2013;369:213-23
RADIUM-223 SYMPTOMATIC SKELETAL EVENTS Sartor et al. Lancet Oncol 2014;15:738-46
RADIUM-223 SYMPTOMATIC SKELETAL EVENTS Sartor et al. Lancet Oncol 2014;15:738-46
RADIUM-223 PREVIOUS DOCETAXEL Improvement in OS irrespective of previous docetaxel Previous docetaxel: HR 0.70 (p=0.002) No previous docetaxel: HR 0.69 (p=0.01) Higher incidence of grade 3-4 thrombocytopenia in previously treated with docetaxel (9% vs 3%) No differences in grade 3-4 anemia or neutropenia Hoskin et al. Lancet Oncol 2014;15:1397-406
RADIUM-223 - CONCLUSIONS Radiopharmaceutical that prolongs overall survival Delay in the occurrence of SREs Good safety profile Potential for combination strategies For symptomatic mcrpc patients, without visceral disease Post-docetaxel or non-candidates ( unfit ) for docetaxel
BONE TARGETED THERAPY ANYTHING ELSE?
CABOZANTINIB Dual blockade of Met and VEGFR-2 Role of Met/HGF in osteoblast/osteoclast activity Prostate cancer: Impressive bone responses Difficult safety profile Pinto A. Cancer Chemother Pharmacol 2014;73:219-22
CABOZANTINIB PHASE II Smith et al. J Clin Oncol 2013;31:412-9
CABOZANTINIB PHASE III COMET TRIALS COMET-1 failed its primary endpoint (OS) 11.0 vs 9.8 months (HR 0.9, p=0.212) PFS: 5.5 vs 2.8 months (HR 0.5, p<0.0001) COMET-2 has been deprioritized by the company
TRAPEZE TRIAL (CRPC WITH BONE METASTASIS) A Docetaxel 75 mg/m 2 Q3W + prednisolone 10 mg OD (Cycles 1 10) B Docetaxel + prednisolone + zoledronic acid 4 mg IV (Cycles 1 10) C Docetaxel + prednisolone (Cycles 1 6) Sr89 150 MBq (Day 28 Cycle 6) 28 days Docetaxel + prednisolone (Cycles 7 10) D Docetaxel + prednisolone + zoledronic acid (Cycles 1 6) Sr89 MBq (Day 28 Cycle 6) 28 days Docetaxel + prednisolone + zoledronic acid (Cycles 7 10) James N, et al. ASCO 2013 [Abstract #LBA5000].
TRAPEZE TRIAL (CRPC WITH BONE METASTASIS) Composite primary outcomes: Bony clinical progression-free survival (CPFS) defined as the first occurrence of: Clinical SRE (no blinded radiological assessment) Death from any cause Bone pain progression Key secondary outcomes: SRE-free interval and total SREs Overall survival James N, et al. ASCO 2013 [Abstract #LBA5000].
TRAPEZE TRIAL PRIMARY OBJECTIVE Outcome Sr89 comparison Zoledronic acid comparison No Sr89 Sr89 No ZA ZA CPFS, n 379 378 381 376 Median, months 8.8 9.8 8.8 9.7 Univariable HR (95% CI) P value Multivariable HR (95% CI) P value 0.84 (0.69 1.02) P = 0.108 0.85 (0.72 0.99) P = 0.036 0.94 (0.81 1.10) P = 0.448 P = 0.46 James N, et al. ASCO 2013 [Abstract #LBA5000].
TRAPEZE TRIAL SECONDARY OBJECTIVES Outcome Sr89 comparison Zoledronic acid comparison No Sr89 Sr89 No ZA ZA SRE free interval, n 379 378 381 376 Median, months 14.7 16.4 13.1 18.1 Univariable HR (95% CI) P value 0.91 (0.74 1.12) P = 0.368 0.76 (0.61 0.93) P = 0.008 Overall survival 16.1 17.1 16.8 16.4 HR 0.97 1.01 (95% CI) P value (0.82 1.15) P = 0.736 (0.85 1.20) P = 0.906 James N, et al. ASCO 2013 [Abstract #LBA5000].
TRAPEZE TRIAL - CONCLUSIONS Sr89 but not zoledronic acid increased bony CPFS (multivariable analysis) Small increase of 1 month, clinically relevant? Zoledronic acid but not Sr89 increased SRE-free interval and decreased total SREs Mostly post-progression No significant differences in toxicity between arms Neither agent had any impact on overall survival
PATIENT PREFERENCE Patients from United Kingdom (n=201) and Sweden (n=200) Nearly 80% would trade off at least 3 months of survival to avoid SREs More than 80% would accept a risk of ONJ up to 9% (the highest tested one)
COMBINATIONS ERA223 TRIAL N=800 mcrpc patients: Asymptomatic or minimally symptomatic No prior CT No visceral disease R A N D O M I Z E ABIRATERONE 1000 mg daily PREDNISONE 5 mg BID PLACEBO ABIRATERONE 1000 mg daily PREDNISONE 5 mg BID RADIUM 223 50 kbq/kg every 4wk PRIMARY OBJECTIVE: Symptomatic skeletal event free survival Secondary objectives: OS, rpfs, time to pain progression, time to opiate use, time to chemotherapy, safety, QoL
COMBINATIONS PEACE-III TRIAL N=560 mcrpc patients: Asymptomatic or minimally symptomatic No visceral disease Previous CHAARTED allowed R A N D O M I Z E ENZALUTAMIDE 160 mg daily PLACEBO ENZALUTAMIDE 160 mg daily RADIUM 223 50 kbq/kg every 4wk PRIMARY OBJECTIVE: rpfs Secondary objectives: OS, first symptomatic skeletal event, time to pain progression, time to opiate use, safety, QoL
COMBINATIONS DOCETAXEL (phase I/IIa) N=60 mcrpc patients with 2 bone mets R A N D O M I Z E 2:1 Radium 223 dichloride 50 kbq/kg q6w + Docetaxel 60 mg/m 2 q3w Docetaxel 75 mg/m 2 q3w PRIMARY OBJECTIVE: Dose-limiting toxicities, safety Secondary objectives: exploratory efficacy measurements (PSA response, ALP response, CTCs), patient self-reports about pain intensity
COMBINATIONS DOCETAXEL (phase I/IIa) ESMO-2014 (Morris et al) 2 cases of febrile neutropenia (both had D alone) 1 case of anemia G3-4 (Ra+D), 2 with G1 (both D) No thrombocytopenia More patients completed Ra+D vs D alone Expanded safety cohort continues as panned Morris et al. ESMO 2014 [Poster presentation]
RADIUM-223 ALTERNATIVE SCHEDULES N=360 mcrpc patients: 2 bone metastasis No visceral disease R A N D O M I Z E Radium 223 dichloride 50 kbq/kg q4w x 6 cycles Radium 223 dichloride 50 kbq/kg q4w x 12 cycles Radium 223 dichloride 80 kbq/kg q4w x 6 cycles PRIMARY OBJECTIVE: Symptomatic skeletal event free survival Secondary objectives: OS, rpfs, time to pain progression, pain improvement rate, safety
RADIUM-223 RE-TREATMENT (phase I-II) N=40 mcrpc patients: Previous therapy with 6 doses of Ra 223 No SAE or grade 3 4 toxicity with Ra 223 No visceral disease Radium 223 dichloride 50 kbq/kg q4w x 6 cycles PRIMARY OBJECTIVE: Safety Secondary objectives: OS, rpfs, time to pain progression, pain improvement rate, time to first symptomatic skeletal event
CONCLUSIONS BONE TARGETED THERAPY AS A CORNERSTONE OF PROSTATE CANCER SREs QoL SURVIVAL PAIN SAFETY ROLE OF COMBINATIONS WITH OTHER ACTIVE AGENTS
THANK YOU FOR YOUR ATTENTION ÁLVARO PINTO Servicio de Oncología Médica Hospital Universitario La Paz IdiPAZ, Madrid