PLAATS VAN DE CHEMOTHERAPIE IN DE BEHANDELING VAN EEN PROSTAATCARCINOOM: EEN UPDATE Daan De Maeseneer, Medisch Oncoloog 1
Overview DEAT PSA/Tumor Burden METASTASES INITIAL DIAGNOSIS & THERAPY ADT CRP SREs/ symptomati c disease iconographic METASTASES Time ADT, androgen deprivation therapy; CRPC, castration-resistant prostate cancer; PSA, prostate-specific antigen; SRE, skeletal-related event. SOURCE: Adapted from Scher H, et al. Urology. 2000;55(3):323 327. 2
Overview DEAT PSA/Tumor Burden INITIAL DIAGNOSIS & THERAPY Abiraterone Docetaxel ADT Time CRP Docetaxel Enzalutamide Abiraterone SREs/ symptomati c disease METASTASE Docetaxel Cabizataxel Abiraterone Enzalutamide ADT, androgen deprivation therapy; CRPC, castration-resistant prostate cancer; PSA, prostate-specific antigen; SRE, skeletal-related event. SOURCE: Adapted from Scher H, et al. Urology. 2000;55(3):323 327. 3 Cabizataxel Radium-223
Overview Docetaxel rechallenge DEAT PSA/Tumor Burden CHAARTED STAMPEDE GTUG-AFU-15 INITIAL DIAGNOSIS & THERAPY TAX-327 FIRSTANA Abiraterone Docetaxel ADT Time TROPIC CRP Docetaxel Enzalutamide Abiraterone SREs/ symptomati c disease METASTASE Docetaxel Cabizataxel Abiraterone Enzalutamide ADT, androgen deprivation therapy; CRPC, castration-resistant prostate cancer; PSA, prostate-specific antigen; SRE, skeletal-related event. SOURCE: Adapted from Scher H, et al. Urology. 2000;55(3):323 327. 4 Cabizataxel Radium-223
Chemotherapy in castration resistant disease 5 EAU guidelines
Chemotherapy in castration resistant disease TAX-327 FIRSTANA TROPIC 6
Chemotherapy CRPC first line TAX-327 FIRSTANA 7
TAX-327 Docetaxel Increased microtubuli polymerization Stabilisation of cytoskeleton Inhibition of mitosis and cell proliferation 1006 mcrpc patients Mitoxantrone 12 mg/m2 q3w Docetaxel 75 mg/m2 q3w Docetaxel 30 mg/m2 q1w 8
TAX-327 OS: Mitoxantrone : 16.5 mo Docetaxel q1w : 17.4 mo (+0.9mo; 9% reduction, NS) Docetaxel q3w : 18.9 mo (+2.4mo; 24% reduction, S) >50% PSA decline Mitoxantrone : 32% Docetaxel q1w : 48% Docetaxel q3w : 45% 9
TAX-327 Standard first-line cytotoxic chemotherapy :docetaxel 75 mg/m2 q3w + prednisone 5 mg BID, up to 10 cycles Survival benefit is shown but palliation is the main target Think about chemotherapy when: PSA level > 114 ng/ml PSA-DT < 55 days presence of visceral metastases Eisenberger et al. 826. Multivariate prognostic nomogram incorporating PSA kinetics in hormone-refractory metastatic prosta cancer (HRPC). Abstract. ASCO Annual Meeting Proceedings (Post-Meeting Edition). J Clin Oncol 2007;25(18S): #5058
Chemotherapy CRPC second line TROPIC 11
TROPIC TROPIC: OS (ITT) for Prednisone + Cabazitaxel 0r Mitoxantrone in mcrpc 30% reduction in risk of death for CBZP vs MP MP CBZP Median OS, mos 12.7 15.1 HR 0.70 95% CI 0.59-0.83 P value <.0001 Combined median follow-up, mos 12.8 + 2.4m OS benefit Points on curve represent censored observations. De Bono JS, et al. Lancet. 2010;376:1147-1154. 12
Chemotherapy CRPC first line TAX-327 FIRSTANA 13
FIRSTANA 14
FIRSTANA 15
FIRSTANA 16
Chemotherapy in castration resistant disease 17 EAU guidelines
Radium-223
Bone Is the Most Common Site of Metastases in Prostate Cancer Patients SITE OF METASTASES 1,2 ~90% <5% 5%-10% Bone ± lymph node/visceral Lymph node only Visceral only Debilitating bone pain is experienced by up to 80% of patients with bone metastases 3 Visceral metastases are less common and may occur in the lungs or liver 4 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. 3. Goh P, et al. Curr Oncol. 2007;14:9 12. 4. Bubendorf L, et al. Hum Pathol. 2000;31:578 583.
Mode of Action: Radium-223 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 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.
Radium-223 Ca 20 Ra 88
SHORT RANGE OF Α-EMITTERS REDUCES BONE MARROW EXPOSURE 1 Marrow Marrow Bone Range of α-particle: (short range 2 to 10 cell diameters 2 ) Radium Ra 223 dichloride Bone Range of β-particle: (long range 10 to 1000 cell diameters 2 ) β-emitter 1. Henriksen G, et al. Cancer Res. 2002;62:3120 3125. 2. Brechbiel MW. Dalton Trans. 2007;43:4918 4928. 22
ALSYMPCA: Study Design PATIENTS (N=921) Confirmed symptomatic CRPC 2 bone metastases No known visceral metastases Post-docetaxel, unfit for docetaxel, or refused docetaxel a STRATIFICATION Total ALP: <220 U/L vs 220 U/L Bisphosphonate use: Yes vs No Prior docetaxel: Yes vs No R 2:1 Radium-223 (50 kbq/kg* IV) 6 injections at 4-week intervals + best standard of care b Placebo (saline) 6 injections at 4-week intervals + best standard of care b 136 centers in 19 countries Planned follow-up is 3 years ALP, alkaline phosphatase; ALSYMPCA, ALpharadin in SYMptomatic Prostate CAncer; CRPC, castrationresistant prostate cancer. a.unfit for docetaxel includes patients who were ineligible for docetaxel, refused docetaxel, or lived where docetaxel was unavailable. b.best standard of care defined as a routine standard of care at each center, e.g., local external beam radiation therapy, corticosteroids, antiandrogens, estrogens (e.g., stilbestrol), estramustine, or ketoconazole. SOURCE: Parker C, et al. N Engl J Med. 2013;369(3):213 223. 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.
ALSYMPCA: Endpoints PRIMARY ENDPOINT Overall survival Whereas other trials included asymptomatic fractures detected by means of periodic radiologic review as skeletal events, ALSYMPCA had no radiographic review and so only symptomatic pathologic bone fractures were captured. Thus symptomatic skeletal event (SSE) was deemed a more clinically relevant term for this measurement. SECONDARY ENDPOINTS Time to total ALP progression a Total ALP response a Time to occurrence of first SSE Total ALP normalization a,b Time to PSA progression a,c Other secondary efficacy endpoints a Safety Quality of life ALP, alkaline phosphatase; PSA, prostate-specific antigen; SSE, symptomatic skeletal event. a.see slides ( Other Secondary Efficacy Endpoints ) for more details. b.defined as return of total ALP to within normal range at 12 weeks [confirmed by two consecutive measurements 2 weeks apart] in patients with total ALP values above upper limit of normal (ULN) at baseline. c. Defined as 25% increase from baseline and an absolute value increase 2 ng/ml at 12 weeks [in patients with no PSA decline from baseline] or 25% increase and an absolute value increase 2 ng/ml above nadir confirmed 3 weeks later, in patients with an initial decrease from baseline. SOURCE: Parker C, et al. N Engl J Med. 2013;369(3):213 223.
ALSYMPCA: Patient Demographics and Baseline Characteristics (ITT Population) CHARACTERISTIC Age, years, Median (range) >75 years, n (%) RADIUM-223 (n=614) 71 (49-90) 171 (28) PLACEBO (n=307) 71 (44-94) 90 (29) Caucasian race, n (%) 575 (94) 290 (94) Total ALP, n (%) <220 U/L 220 U/L Current use of bisphosphonates, n (%) Yes No Any prior use of docetaxel, n (%) Yes No ECOG PS, n (%) 0 1 2 348 (57) 266 (43) 250 (41) 364 (59) 352 (57) 262 (43) 165 (27) 371 (60) 77 (13) 169 (55) 138 (45) 124 (40) 183 (60) 174 (57) 133 (43) 78 (25) 187 (61) 41 (13) 57% post-docetaxel ALP, alkaline phosphatase; ECOG PS, Eastern Cooperative Oncology Group Performance Status; ITT, intention-to-treat. SOURCE: Parker C, et al. N Engl J Med. 2013;369(3):213 223.
ALSYMPCA: Patient Demographics and Baseline Characteristics CHARACTERISTIC WHO ladder for cancer pain, n (%) 1 2 3 Extent of disease, n (%) <6 metastases 6-20 metastases >20 metastases Superscan EBRT within 12 weeks of screening, n (%) Yes No Hemoglobin (g/dl), Median (range) [normal range: 13.4-17 g/dl] Albumin (g/l), Median (range) [normal range: 36-45 g/l] Total ALP (U/L), Median (range) [normal range: 35-105 U/L] LDH (U/L), Median (range) [normal range: 115-255 U/L] PSA (μg/l), Median (range) [normal range: 0-3.999 μg/l] ITT, intention-to-treat; WHO, World Health Organization. SOURCE: Parker C, et al. N Engl J Med. 2013;369(3):213 223. RADIUM-223 (n=614) 257 (42) 151 (25) 194 (32) 100 (16) 262 (43) 195 (32) 54 (9) 99 (16) 515 (84) PLACEBO (n=307) 137 (45) 78 (25) 90 (29) 38 (12) 147 (48) 91 (30) 30 (10) 48 (16) 259 (84) 12.2 (8.5-15.7) 12.1 (8.5-16.4) 40 (24-53) 40 (23-50) 211 (32-6431) 223 (29-4805) 315 (76-2171) 336 (132-3856) 146 (3.8-6026) 173 (1.5-14500)
ALSYMPCA Updated Analysis: Radium-223 Significantly Improved OS 100 80 Survival, % 60 40 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 20 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 The updated analysis confirmed the 30% reduction in risk of death (HR=0.70) for patients in the radium-223 group compared with placebo. CI, confidence interval; HR, hazard ratio; OS, overall survival. SOURCE: Parker C, et al. N Engl J Med. 2013;369(3):213 223. Months Since Randomization
ALSYMPCA Updated Analysis: Radium-223 Improved OS Across All Patient Subgroups 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 score of 1 on the WHO ladder for cancer pain. SOURCE: Parker C, et al. N Engl J Med. 2013;369(3):213 223.
Overview DEAT PSA/Tumor Burden INITIAL DIAGNOSIS & THERAPY Abiraterone Docetaxel ADT Time CRP Docetaxel Enzalutamide Abiraterone SREs/ symptomati c disease METASTASE Docetaxel Cabizataxel Abiraterone Enzalutamide ADT, androgen deprivation therapy; CRPC, castration-resistant prostate cancer; PSA, prostate-specific antigen; SRE, skeletal-related event. SOURCE: Adapted from Scher H, et al. Urology. 2000;55(3):323 327. 29 Cabizataxel Radium-223
Chemotherapy in hormone sensitive disease Hypothesis : Chemotherapy (docetaxel) added at the time of starting androgen deprivation therapy for hormone naïve (metastatic) prostate cancer will prolong survival Androgen Deprivation Therapy Regression Re-emergence 30
Chemotherapy in hormone sensitive disease CHAARTED STAMPEDE GTUG-AFU- 15 31
CHAARTED 32
CHAARTED 33
CHAARTED 34
CHAARTED 35
GTUG-AFU- 15 A randomised, open-label phase 3 trial comparing ADT alone or with docetaxel in non-castrate metastatic prostate cancer n=385 Patients with metastatic prostate cancer Karnofsky score 70% Life expectancy 3 months Adequate hepatic, haematological, and renal function No previous chemotherapy R 1:1 n=192 ADT*+ docetaxel** n=193 ADT* 29 centres in France and one centre in Belgium *ADT consisted of orchiectomy or luteinising hormone-releasing hormone agonists, alone or combined with non-steroidal antiandrogens. **75 mg/m² intravenous docetaxel in a 250 cm³ 5% glucose solution in the course of 1 h on the first day of each 21-day cycle, for up to 9 cycles. ADT, androgen deprivation therapy; bpfs, biochemical progression-free survival; cpfs, clinical progression-free survival; PSA, prostate specific antigen; R, randomisation. Gravis G, et al. Lancet Oncol 2013; 14(2) 149 58. 36
GETUG-15 HR 0.75, 95% CI 0.59 0.94 p=0.015 HR 1.01, 95% CI 0.75 1.36 p=0.955 Overall survival (OS) Clinical progression-free survival (PFS) Gravis G et al. Lancet Oncol 2013; 14:149-58 37
Patients with High-Volume disease GETUG-15 HR 0.88, 95% CI 0.68 1.14 p=0.3 Patients with Low-Volume disease Overall survival (OS) Gravis G, et al. ADT Plus Docetaxel Versus ADT Alone in Metastatic Non castrate Prostate Cancer: Impact of Metastatic Burden and Long-term Survival Analysis of the Randomized Phase 3 GETUG-AFU15 Trial. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.11.005 38
GETUG-15 applying CHAARTED definition Gravis G, et al. ADT Plus Docetaxel Versus ADT Alone in Metastatic Non castrate Prostate Cancer: Impact of Metastatic Burden and Long-term Survival Analysis of the Randomized Phase 3 GETUG-AFU15 Trial. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.11.005 39
STAMPEDE 40
STAMPEDE 41
STAMPEDE 42
STAMPEDE 43
STAMPEDE 44
STAMPEDE All patients James ND et al. Lancet 2016; 387:1163-77 45
STAMPEDE All patients Median OS was increased by 10 months James ND et al. Lancet 2016; 387:1163-77 46
Chemotherapy in hormone sensitive disease CHAARTED STAMPEDE GTUG-AFU- 15 47
Results M1 patients 9% survival benefit at 4yr 16% FFS benefit at 4yr Addition of docetaxel or bisphosphonates to standard of care in men with localised or metastatic, hormone-sensitive prostate cancer: a systematic review and metaanalyses of aggregate data. Lancet Oncol 2016; 17: 243 56
Results M0 patients NS survival benefit at 4yr 8% FFS benefit at 4yr Addition of docetaxel or bisphosphonates to standard of care in men with localised or metastatic, hormone-sensitive prostate cancer: a systematic review and metaanalyses of aggregate data. Lancet Oncol 2016; 17: 243 56
2017 EAU ESTRO SIOG guidelines on Prostate Cancer M1 disease Mottet N et al. EAU guidelines on prostate cancer, update 2017; http://uroweb.org/guideline/prostate-cancer/ (accessed Augustt 2017)
Docetaxel vs Abi STAMPEDE Matthew Sydes, ESMO 2017
Conclusions Sequence of therapy in CRPC needs to be individualized, there is no one size fits all. Optimal sequences include both AR targeted agents and chemotherapy Upfront therapy with docetaxel (and abiraterone) improves survival and alters patterns of care
Consequences of LATITUDE and STAMPEDE in Europe In many cases, treatment sequence in metastatic PCa likely to be as follows: 1t line 2nd line 3rd line OR ABI à DOC àenza or CABA DOC à ABI à ENZA or CABA Need to define what is the optimal sequence (AR-targeted agent or CABA in 3rd line)
CARD study A practice changing trial R Metastatic pts rapidly with an AR-targeted agent ( 12 months, before or after Docetaxel n=324 Stratification factors: ECOG PS (0/1 vs 2), time to progression ( 6 vs 6 12 mo), timing of AR-targeted agent (before vs after DOC) A N D O M I Z E 1:1 CABAZITAXEL n=162 Swith to another AR-targeted agent (ABI or ENZA depending of first therapy) n=162 Primary endpoint: radiographic PFS Sponsor: Sanofi Secondary endpoints: PSA response, ECOG PS, PFS (clinical or radiological), objective tumor response, pain, QoL, time to SSEs, OS, safety, biomarkers NCT02485691. ClinicalTrials.gov.