Novità nella terapia medica del
carcinoma prostatico
Francesco Boccardo UOC Clinica di Oncologia
Medica
1. Carcinoma prostatico metastatico ormono-sensibile (mHSPC) (Carcinoma prostatico oligometastatico )
2. Carcinoma prostatico metastatico resistente alla castrazione (mCRPC)
3. M0 CRPC
4. Marker predittivi di risposta alle terapie
5. Nuovi bersagli terapeutici
Long-term survival analysis of the CHAARTED Trial
HR 0.63
P<0.001 HR 1.04
P=0.86 HR 0.63
P<0.001 HR 0.86
P=0.55
HR 0.72
P=0.37 HR 1.25
P=0.55
Kyriakopoulos C. et al. J Clin Oncol 2018
M1 «de novo» Patients
Prior local therapy
GETUG-AFU15/CHAARTED
‒ Combined Analysis
Study Low volume High volume
CHAARTED 100 / 277 299 / 513
GETUG-AFU15 95 / 202 147 / 183
Total 195 / 479 446 / 696
HR
(homog between trials)
1.03 (0.77 – 1.38) P=0.80
0.68 (0.56 – 0.82) P<0.0001 Interaction HR (volume x D) = 0.66
Interaction P=0.017 (high power) There is evidence of interaction
Conditional power to detect an effect is very low in the low-volume group However, follow-up is still relatively short for low volume
D, docetaxel; HR, hazard ratio; homog, homogenicity
Slide presented by Laurence Colette (EORTC statistician) at EAU 2018 - Gravis G, et al. Eur Urol. 2018.
Carcinoma prostatico metastatico ormono-sensibile (mHSPC)
STAMPEDE, 2016
James ND, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet (London, England). 2016; 387(10024):1163-1177
Beneficio di 17 mesi in PFS e 10 mesi in OS con ADT + docetaxel rispetto alla sola ADT
Carcinoma prostatico metastatico ormono-sensibile (mHSPC)
QUESITO GRADE:
Nei pazienti con malattia metastatica (M1) ormono-sensibile, “high-volume” alla diagnosi secondo i criteri CHAARTED, che non abbiano controindicazioni alla chemioterapia, è raccomandabile l’associazione del Docetaxel up-front alla terapia androgeno-soppressiva?
RACCOMANDAZIONE:
Nei pazienti con malattia metastatica (M1) ormono-sensibile, “high-volume” alla diagnosi secondo i criteri CHAARTED, l’associazione up-front di Docetaxel (6 cicli) alla terapia androgeno- soppressiva deve essere presa in considerazione.
Forza della raccomandazione: POSITIVA FORTE Qualità delle evidenze: MODERATA
High-volume: presenza di metastasi viscerali ovvero di 4 o più metastasi a livello scheletrico di cui almeno una localizzata in sedi diverse dalla colonna vertebrale e bacino.
Abiraterone in High-risk M1 pts:
STAMPEDE confirms LATITUDE
OS
PSA Progression (FFS) SSE
PFS
HR 0.54 (0.41-0.70) p<0.001
Hoyle A, ESMO 2018
Abiraterone in Low-risk M1 pts:
New data from STAMPEDE
PFS OS
SSE PSA Progression (FFS)
HR: 0.63 (0.42-0.95) P=0.027
Hoyle A, ESMO 2018
M1 HSPC :
1) ADT solo ai pazienti unfit o unwilling?
2) DOPPIETTA: A TUTTI O SOLO HIGH VOLUME/HIGH RISK?
3) Quale doppietta? ADT + ABI o ADT + DOCE? (ADT+APA o ADT+ENZA) 4) Doppietta :solo pazienti de novo o anche i pazienti ricaduti dopo terapia primaria
5) tre meglio di due?
Comparing CHAARTED High Volume Patients and LATITUDE Patients
Sydes M et al, ESMO 2017, abstract LBA31_PR
Sydes M et al, ESMO 2017, abstract LBA31_PR
Sydes M et al, ESMO 2017, abstract LBA31_PR
Sydes M et al, ESMO 2017, abstract LBA31_PR
PRO: Indirect comparison of LATITUDE and CHAARTED
Patient function (FACT-P) Pain (BPI)
Feyerabend S, et al. ASCO GU 2018
Conclusions (?)
The association of abiraterone and prednisone doesn’t appear to improve OS compared to docetaxel
Docetaxel and abiraterone have distinct side effects but both require a strict follow-up policy
The decision making process should consider patient comorbidities
and preference, disease characteristics, drug side effects, availability
and costs
Slide 21
Presented By Kim Chi at 2019 ASCO Annual Meeting
TITAN Study Design
Presented By Kim Chi at 2019 ASCO Annual Meeting
TITAN rPFS: Apalutamide Significantly Reduced Risk of Radiographic Progression or Death by 52%
Presented By Kim Chi at 2019 ASCO Annual Meeting
TITAN OS: Apalutamide Significantly Reduced the Risk <br />of Death by 33%
Presented By Kim Chi at 2019 ASCO Annual Meeting
TITAN OS Benefit Consistent Across Subgroups
Presented By Kim Chi at 2019 ASCO Annual Meeting
TITAN Health-Related Quality of Life Was Preserved With Apalutamide + ADT and Not Different From Placebo + ADT
Presented By Kim Chi at 2019 ASCO Annual Meeting
TITAN Conclusions (cont’d)
Presented By Kim Chi at 2019 ASCO Annual Meeting
Slide 22
Presented By Christopher Sweeney at 2019 ASCO Annual Meeting
ENZAMET Treatment
Presented By Christopher Sweeney at 2019 ASCO Annual Meeting
Patient characteristics
Presented By Christopher Sweeney at 2019 ASCO Annual Meeting
Primary endpoint: Overall survival
Presented By Christopher Sweeney at 2019 ASCO Annual Meeting
Secondary Endpoints: Progression–free survival (PCWG2)
Presented By Christopher Sweeney at 2019 ASCO Annual Meeting
Concurrent Docetaxel: Prespecified Subgroup of Interest<br />(Biology and Treatment Implications)
Presented By Christopher Sweeney at 2019 ASCO Annual Meeting
Conclusion
Presented By Christopher Sweeney at 2019 ASCO Annual Meeting
Clinical interpretation
Presented By Christopher Sweeney at 2019 ASCO Annual Meeting
Overall survival: prostate radiotherapy in M1 oligometastatic disease (STAMPEDE)
0.0 0.2 0.4 0.6 0.8 1.0
Overall survival
410 (1) 405 (4) 399 (12) 366 (12) 301 (19) 242 (10) 200 (15) 137 (11) 77 (5) 24 SOC+RT
409 (5) 400 (9) 387 (17) 361 (17) 265 (12) 217 (22) 155 (16) 110 (8) 67 (5) 25
SOC Number of patients (events)
0 6 12 18 24 30 36 42 48 54
Time from randomisation (Months) trt = SOC by Kaplan Meier
trt = SOC+RT by Kaplan Meier SOC by flexible parametric model SOC+RT by flexible parametric model
0.0 0.2 0.4 0.6 0.8 1.0
Overall survival
553 (10) 537 (38) 487 (48) 424 (59) 282 (30) 216 (31) 146 (19) 90 (14) 44 (5) 20 SOC+RT
567 (11) 547 (42) 500 (58) 428 (41) 312 (27) 245 (43) 161 (20) 100 (7) 48 (3) 13
SOC Number of patients (events)
0 6 12 18 24 30 36 42 48 54
Time from randomisation (Months) trt = SOC by Kaplan Meier
trt = SOC+RT by Kaplan Meier SOC by flexible parametric model SOC+RT by flexible parametric model
Low burden
High burden
HR: 0.68 (95% CI 0.52-0.90); p=0.007 3 year OS (%):
SOC = 73%
SOC+RT = 81%
HR: 1.07 (95% CI 0.90-1.28); p=0.420 3 year OS (%):
SOC = 54%
SOC+RT = 53%
SOC+RT
SOC
SOC+RT SOC
Parker C, ESMO 2018 and Lancet 2018
THE IMPORTANCE OF IMAGING TO CORRECTLY CATEGORISE OLIGOMETASTASES
a) Conventional
99mTc-MDP planar scintigraphy shows bone metastases in right scapula (black arrow),left lower anterior ribcage (red arrow),and right proximal femoral shaft (blue arrow) b) 18-F NaF PET/CT obtained
shortly afterward shows greater burden of
metastases
18F-NaF: sodium fluoride tracer; 99mTc-MDP,technetium99m-methyldiphosphonate;CT,computed tomography;PET,positronemissiontomography
KulshresthaRKet al.J Nucl MedTechnol2016; 44:217-222 5
How should we stage M0 CRPC?
PROSPER/SPARTAN/ARAMIS Study Design:
in High-Risk M0 CRPC
Placebo Estimated Enrollment:
1,500
•M0 CRPC
•PSA doubling time of ≤10 months
•ECOG PS 0-1
ENZA/APA/DARO
Primary endpoints:
Metastasis-free survival
Key secondary endpoints:
OS
Time to first SSE Time to initiation of first
cytotoxic chemo Time to pain
progression
2 1 R
Similar trials: Enzalutamide (PROSPER), Apalutamide (SPARTAN) and Darolutamide (ARAMIS)
• 72% reduction of distant progression or death
• Median MFS: APA 40.5 vs PBO 16.2 months
• 24-month additional MFS benefit
SPARTAN
1PROSPER
2• 71% reduction of distant progression or death
• Median MFS: ENZA 36.6 vs PBO 14.7 months
• 22-month additional MFS benefit
1. Smith MR, et al. N Engl J Med. 2018;378:1408-18.
2. Hussain M, et al. N Engl J Med. 2018;378:2465-74.
SPARTAN and PROSPER: primary endpoint – MFS
HR (95% CI): 0.28 (0.23–0.35) p < 0.0001
ENZA, 36.6 mo (median)
PBO, 14.7 mo (median)
HR (95% CI): 0.29 (0.24–0.35) p < 0.001
CI, confidence interval; HR, hazard ratio; mo, months.
Fizazi K, NEJM 2019
ARAMIS: MFS & OS
HR 0.41
(95% CI 0.34–0.50) P<0.0001
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0
0 4 8 12 16 20 24 28 32 36 40 44 48 Months
955 554
817 368
675 275
506 180
377 117
262 75
189 50
116 29
68 12
37 4
18 0
2 0
0 0 Darolutamide
Placebo
Survival Probability
Number of subjects at risk
Darolutamide:
40.4 months (median)
Placebo:
18.4 months (median)
o
59% risk reduction of distant metastases or death Median follow up time at primary analysis was 17.9 mos
83%
73%
Fizazi K, et al. 2019 Genitourinary Cancers Symposium. Abs 140
ARAMIS: Treatment-Related AEs of Interest
Adverse event, all grades, n (%) Darolutamide (N = 954) Placebo (N = 554)
Fatigue/asthenic conditions 151 (15.8) 63 (11.4)
Dizziness (including vertigo) 43 (4.5) 22 (4.0)
Cognitive disorder 4 (0.4) 1 (0.2)
Memory impairment 5 (0.5) 7 (1.3)
Seizure (any event) 2 (0.2) 1 (0.2)
Bone fracture 40 (4.2) 20 (3.6)
Falls (including accident) 40 (4.2) 26 (4.7)
Hypertension 63 (6.6) 29 (5.2)
Coronary artery disorders 31 (3.2) 14 (2.5)
Heart failure 18 (1.9) 5 (0.9)
Rash 28 (2.9) 5 (0.9)
Weight decreased (any event) 34 (3.6) 12 (2.2)
Hypothyroidism 2 (0.2) 1 (0.2)
M0 CRPC
To treat or not
to treat …
Carcinoma prostatico metastatico resistente alla castrazione (mCRPC)
Qualità dell’evidenza
SIGN
Raccomandazione
Forza della raccomandazione
clinica
Molto Bassa
Nei pazienti affetti da malattia metastatica resistente alla castrazione, allo stato attuale delle conoscenze, non dovrebbe essere preferita una sequenza terapeutica rispetto ad altre.
La scelta dei trattamenti da utilizzare dovrebbe essere effettuata sulla base delle caratteristiche della malattia, della sintomaticità/asintomaticità del paziente, delle sue preferenze, dell’idoneità a ricevere un trattamento chemioterapico.
Negativa debole
?
Carcinoma prostatico metastatico resistente alla castrazione (mCRPC)
CTC e AR-V7 come marker predittivo di risposta agli ARSi
Antonarakis ES, et al. Clinical Significance of Androgen Receptor Splice Variant-7 mRNA Detection in Circulating Tumor Cells of Men With Metastatic Castration-Resistant Prostate Cancer Treated With First- and Second-Line Abiraterone and Enzalutamide. Jorunal of Clinical Oncology. 2017; 35(19):2149-2156
From: Assessment of the Validity of Nuclear-Localized Androgen Receptor Splice Variant 7 in Circulating Tumor Cells as a Predictive Biomarker for Castration-Resistant Prostate Cancer
JAMA Oncol. 2018;4(9):1179-1186. doi:10.1001/jamaoncol.2018.1621
From: Assessment of the Validity of Nuclear-Localized Androgen Receptor Splice Variant 7 in Circulating Tumor Cells as a Predictive Biomarker for Castration-Resistant Prostate Cancer
JAMA Oncol. 2018;4(9):1179-1186. doi:10.1001/jamaoncol.2018.1621
Robinson D., et al. Integrative Clinical Genomics of Advanced Prostate Cancer. Cell. 2015; 161(5):1215-1228
Carcinoma prostatico e nuovi bersagli terapeutici
49% 71% 23%
18% 35%
Cattrini C., et al. Targeting androgen-independent pathways: new chances for patients with prostate cancer?. Critical Reviews in Oncology/Hematology.
2017; 118:42-53
Carcinoma prostatico e nuovi bersagli
terapeutici
Carcinoma prostatico e nuovi bersagli terapeutici
TARGET DRUG REFERENCES
PARP-1 Olaparib, veliparib (Hussain et al., 2016; Mateo et al., 2015)
AKT Ipatasertib, AZD5363 (Crabb et al., 2017; De Bono, J. S. et al., 2016; Kolinsky et al., 2017)
Hsp27 Apatorsen (Chi et al., 2017)
Hh Itraconazole (Antonarakis et al., 2013)
PD-1 Durvalumab, pembrolizumab (Graff et al., 2016a; Hansen et al., 2016; Karzai et al., 2017)
Cattrini C., et al. Targeting androgen-independent pathways: new chances for patients with prostate cancer?. Critical Reviews in Oncology/Hematology.
2017; 118:42-53
Niraparib ( Smith et al, 2019)
KEYNOTE-365
Long-lasting complete response after Ipilimumab in CRPC
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