Novità nella terapia medica del Carcinoma prostatico

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Novità nella terapia medica del

carcinoma prostatico

Francesco Boccardo UOC Clinica di Oncologia

Medica

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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

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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

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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.

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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

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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.

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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

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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

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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?

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Comparing CHAARTED High Volume Patients and LATITUDE Patients

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Sydes M et al, ESMO 2017, abstract LBA31_PR

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Sydes M et al, ESMO 2017, abstract LBA31_PR

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Sydes M et al, ESMO 2017, abstract LBA31_PR

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Sydes M et al, ESMO 2017, abstract LBA31_PR

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PRO: Indirect comparison of LATITUDE and CHAARTED

Patient function (FACT-P) Pain (BPI)

Feyerabend S, et al. ASCO GU 2018

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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

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Slide 21

Presented By Kim Chi at 2019 ASCO Annual Meeting

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TITAN Study Design

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TITAN rPFS: Apalutamide Significantly Reduced Risk of Radiographic Progression or Death by 52%

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TITAN OS: Apalutamide Significantly Reduced the Risk <br />of Death by 33%

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TITAN OS Benefit Consistent Across Subgroups

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TITAN Health-Related Quality of Life Was Preserved With Apalutamide + ADT and Not Different From Placebo + ADT

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TITAN Conclusions (cont’d)

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Slide 22

Presented By Christopher Sweeney at 2019 ASCO Annual Meeting

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ENZAMET Treatment

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Patient characteristics

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Primary endpoint: Overall survival

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Secondary Endpoints: Progression–free survival (PCWG2)

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Concurrent Docetaxel: Prespecified Subgroup of Interest<br />(Biology and Treatment Implications)

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Conclusion

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Clinical interpretation

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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

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THE IMPORTANCE OF IMAGING TO CORRECTLY CATEGORISE OLIGOMETASTASES

a) Conventional

^99m

Tc-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

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How should we stage M0 CRPC?

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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)

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• 72% reduction of distant progression or death

• Median MFS: APA 40.5 vs PBO 16.2 months

• 24-month additional MFS benefit

SPARTAN

¹

PROSPER

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.

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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%

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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)

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M0 CRPC

To treat or not

to treat …

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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

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?

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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

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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

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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

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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%

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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

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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)

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KEYNOTE-365

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Long-lasting complete response after Ipilimumab in CRPC

0 20 40 60 80 100 120 140

1 2 3 4 5 6 7 8 9 10111213141516171819202122232425262728293031

Cabel L, J Immunother Cancer 2017; 5: 31 2011:

mCRPC progressing post-docetaxel Pain requiring opioids

Ipilimumab + RXT to 1 bone 2018:

No detectable disease at 7 years+

PSA

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