Current role of chemotherapy in hormone-naïve patients · 2017. 11. 9. · M1 HSPC Stratification-Low vs High volume-Age 70 yrs-MAB 30 days-SER prevention-Adjuvant

Current role of chemotherapy in hormone-naïve patients

Elena Castro

Spanish National Cancer Research Centre

Lugano, 17 October 2017

Siegel, Ca Cancer J Clin,2017

Buzzoni, Eur Urol, 2015

-Aprox 15-20% of new PrCa diagnosis present with advanced disease:

- 4-5% distant metastasis EU, USA

- Prevalence of metastasis at diagnosis varies geographically, depending

on screening programs, access to health system, etc

- 80-75% patients with metastatic disease will present it after recurrence

following treatment for localized disease.

Local DIsease

M0

Metastatic

Disease

M1

Recurrence

M1

CPRC_M1

CPRC_M1

20%

80%

-ADT may induce biochemical and clinical responses in 90% of patients

- After 24-36 months progression to Castration Resistance Prostate Cancer ocurrs

-ADT may induce adaptation of hormone-sensitive cells and/or selection of AR-

independent clones

Hellerstdet, CA Cancer J Clin, 2002

Zong, Nat Rev Urol, 2013

Metastatic

No Chemo

ECOG ≤2

n=1006

Docetaxel 75mg/m2 q3w +

Prednisone 5 mg /12h

Mitoxantrone 12mg/m2 q3w +


Docetaxel 30 mg/m2 1w +


Study end points:• Primary: OS• Secondary: Pain reduction, QoL, ≥50% decline, tumour response

Improved OS (18.9m vs 16.5 m, p<0.001)≥ 50% PSA decline (45% vs 32 %, p<0.001)

Reduction in pain: 35 % vs 22 % (p=0.01)

QoL:22% vs 13% (p=0.009)

DocetaxelTAX-327

Tannock, NEJM, 2004

N=335

N=334

N=337

Would the adition of docetaxel to ADT for M1 hormone-sensitive

PrCa delay the progression to mCRPC and improve survival?

M1 HSPC

Stratification

- Previous TT

-Glass risk group-Apendicular vs axial disese

-Performance status

-PSA < or > 65ng/dL

-Gleason <or >8

Docetaxel 75mg/m2 q3w

(No prednisone) up to 9 cycles

+

ADT

ADT alone

Study end points:• Primary: OS• Secondary: Clinical and PSA Progression Free Survival

GETUG 15 study

Gravis, Lancet Oncol, 2013

N=193

N=192

Median OS: 58.4 vs 52.2 months, p=0.955)

3y OS: 64.2% vs 62.9%

72% de novo M1 Median follow-up: 50 months

Median 8 cycles

bPFS: 22.9 vs 12.9, HR 0.72, p=0.005 cPFS: 20.5 vs 15.4, HR 0.75, p=0.015

M1 HSPC

Stratification-Low vs High volume

- Age <70 vs >70 yrs

-MAB <30 vs >30 days

-SER prevention

-Adjuvant ADT <12

vs<12 months

Docetaxel 75mg/m2 q3w

(No prednisone) up to 6 cycles

+

ADT

ADT alone

Study end points:• Primary: OS• Secondary: Time to CRPC and to clinical progression

CHAARTED study

Seeney,NEJMl, 2015

N=397

N=393

ADT allowed up to 120 days prior to randomization

Median follow-up: 28.9 months

73% de novo M1

27% recurrent disease

Improved OS: 57.6 vs 44 months (HR 0.61, p<0.001)

cPFS: 33 vs 19.8 monts (HR, 0.49 p<0.001)

Time to CRPC: 20.2 vs 11.7 months (HR

0.56,p<0.001)

ADT + docetaxel was beneficial in all subgroups

Seeney,NEJMl, 2015

STAMPEDE: Docetaxel +Pred + ADT vs ADT

Recruitment: Oct-2005 to Mar-2013 Patients: 1184 SOC

592 SOC+DocP

Allocation ratio:2:1

Courtesy of Dr Sydes

STAMPEDE

SOC (ADT+/-RT)

N=1184

Study end points:• Primary: OS• Secondary: PFS

61% M1 and 39% M0

Median follow-up: 43 months

Docetaxel 75mg/m2 q3w + Prednisone 5mg/12h

up to 6 cycles + SOC

N=592

Metastasis at presentation

OS: 60 vs 45 months

(HR 0.76, p=0.005)

OS: 81 vs 71 months, (HR 0.78, p=0.006)

SOC+DOC

SOC

Sweeney,NEJMl, 2015

Do all patients benefit the same?

HIGH volume disease

-Visceral metastasis or

-≥ 4 bone metastasis with ≥1 beyond vertebral bodies and pelvis

CHAARTED_update ESMO 2016

-Benefit on OS in High Volume

- Low Volume: Benefit on time to CRPC: 31 months (ADT+Doce) vs 27monts (ADT),

p=0.03

OS High Volume Disease

(48%)

OS Low Burden Disease

- 20% reduction in the risk of death in the HVD group (No significant)

- Patients with LVD did not benefit form early docetaxel.

GETUG-AFU15 post hoc analysis

Puente, Ther Adv Me Oncol, 2017

METAANALYSIS M1

2993 patients included

-Addition of Docetaxel to ADT improved OS.

-HR 0.77 and 9% absolute improvement in survival at 4 years.

-Addition of Docetaxel to ADT improved PFS.

-HR 0.64 and 15% absolute reduction in failure at 4 years.

Vale, Lancet Oncol, 2016

Overall Survival PFS

METAANALYSIS M0

2121patients included

-Addition of Docetaxel to ADT did not improved OS.

-HR 0.87, p=0.218.

-Addition of Docetaxel to ADT improved PFS.

-HR 0.70 and 8% absolute reduction in failure at 4 years.

Overall Survival PFS

CONCLUSIONS

-Addition of Docetaxel to ADT should be considered standard of care for M1 Hormone-

Sensitive Prostate Cancer.

- Further evidence on the impact of Docetaxel in survival is needed to recomend the

addition of docetaxel to ADT for M0 patients

The addition of abiraterone acetate to ADT significantly increases OS and rPFS in M1 HSPC

LATITUD trial

Fizazi, NEJM, 2017

Slide 30

Presented By Nicholas James at 2017 ASCO Annual Meeting

OK…….SO WHAT SHOULD WE USE?

Reference

STAMPEDE: SOC+AAP vs SOC+DocP

-Evidence about whether to

give both is pending

-566 patients randomised

contemporaneously to either

research arm:

ESMO2017

Patients: 189 SOC+DocP

377 SOC+AAP

Recruitment: Nov2011-Mar2013

Courtesy of Matt Sydes. ESMO 2017

Populations in each comparison

SOC+DocP vs SOC+AAP

M1 60%

Age 66 yr median

PSA 56 ng/ml median

Accrue Nov-2011 to Mar-2013

Freeze Mar-2017

SOC+DocP vs SOC

M1 61%

Age 65 yr median

PSA 68 ng/ml median

Accrue Oct-2005 to Mar-2013

Freeze May-2015

SOC+AAP vs SOC

M1 52%

Age 67 yr median

PSA 53 ng/ml median

Accrue Nov-2011 to Jan-2014

Freeze Mar-2017


HR (95%CI) P-valInteractn

test

All 1.16 (0.82 to 1.65) 0.40

M0 1.51 (0.58 to 3.93) 0.400.69

M1 1.13 (0.77 to 1.66) 0.53

Key:HR<1 favours SOC+AAPHR>1 favours SOC+DocP

Interactn = test for interaction (heterogeneity of treatment effect)

SOC+DocP SOC+AAP

Events Pts Events Pts

All 44 189 105 377

M0 6 74 16 150

M1 38 115 89 227

SOC+AAP

SOC+DocP

Overall Survival


Cause-specific survival

Sub-HR

(95%CI)P-val

All 1.02 (0.70 to 1.49) 0.92

Status SOC+DocP SOC+AAP

N % N %

Alive 145 77% 272 72%

Dead 44 23% 105 28%

PCa Death 40 21% 86 23%

Other cause 4 2% 19 5%

Competing risks approach

SOC+DocP death: 91% PCa and 9% otherSOC+AAP deaths: 82% PCa and 18% other



PSA Failure-free survival


test

All 0.51 (0.39 to 0.67) <0.001

M0 0.34 (0.16 to 0.69) 0.0030.17

M1 0.56 (0.42 to 0.75) <0.001

SOC+AAP

SOC+DocP



SOC+DocP SOC+AAP


All 97 189 122 377

M0 18 74 13 150

M1 79 115 109 227


Progression-free survival


test

All 0.65 (0.48 to 0.88) 0.005

M0 0.42 (0.17 to 1.05) 0.060.32

M1 0.69 (0.50 to 0.95) 0.02



SOC+DocP SOC+AAP


All 72 189 103 377

M0 10 74 9 150

M1 62 115 94 227

SOC+AAP

SOC+DocP

PFS = FFS ignoring PSA failure Courtesy of Matt Sydes. ESMO 2017

Metastatic progression-free survival

HR (95%CI) P-val

Interactn

test

All 0.77 (0.57 to 1.03) 0.08

M0 0.91 (0.42 to 2.01) 0.820.74

M1 0.76 (0.55 to 1.04) 0.09



SOC+DocP SOC+AAP


All 71 189 118 377

M0 10 74 18 150

M1 61 115 100 227

SOC+AAP

SOC+DocP

MPFS = new or progression of metastases

Symptomatic skeletal events


test

All 0.83 (0.55 to 1.25) 0.38

M0 1.28 (0.24 to 6.67) 0.770.65

M1 0.82 (0.53 to 1.25) 0.35

SOC+AAP

SOC+DocP



SOC+DocP SOC+AAP


All 36 189 63 377

M0 2 74 5 150

M1 34 115 58 227

Exposure to relapse treatments after FFS event

Note:

• Randomisation: Nov-2011 to Jan-2013

• Data freeze: Feb-2017

Docetaxel started after FFS event AR-targeted therapy started after FFS event

SOC+AAP

SOC+DocP

FFS event FFS event

Note:

• Relapse treatments at investigators’ discretion

• Access to relapse treatments may depend on:

• Metastatic status at event

• Calendar year of event

• Suspect under reporting of third-line therapies and onwards

SOC+AAP

SOC+DocP

Summary

Strong evidence favouring AAP

Toxicity profiles quite different and well known

Weak evidence favouring AAP

No good evidence of a difference

FavoursSOC+AAP

FavoursSOC+DocP

Hazard ratio

Metastatic progression-free

survival

Progression-free survival

PSA Failure-free survival

Symptomatic skeletal events

Cause-specific survival

Overall survival

Head-to-head data in 566 pts (Nov-2011 to Mar-2013)


Safety population SOC+DocP SOC+AAP

Patients included in adverse event analysis 172 (91%) 373 (>99%)

Grade 1+ AE 172 (100%) 370 (99%)

Grade 3+ AE 86 (50%) 180 (48%)

Grade 3+ AEs by category (incl. expected AEs)

Endocrine disorder (incl. hot flashes, impotence) 15 (9%) 49 (13%)

Febrile neutropenia 29 (17%) 3 (1%)

Neutropenia 22 (13%) 4 (1%)

Musculoskeletal disorder: 9 (5%) 33 (9%)

Cardiovascular (incl. hypertension, MI, cardiac dysrhythmia): 6 (3%) 32 (9%)

Gastrointestinal disorder: 9 (5%) 28 (8%)

Hepatic disorder (incl. increased AST, increased ALT): 1 (1%) 32 (9%)

General disorder (incl. fatigue, oedema): 18 (10%) 21 (6%)

Respiratory disorder (incl. breathlessness): 12 (7%) 11 (3%)

Renal disorder 5 (3%) 20 (5%)

Lab abnormalities (incl. hypokalaemia): 9 (5%) 11 (3%)

Adverse events – worst toxicity ever


1 year SOC+DocP SOC+AAP

Patients in safety dataset 136 323

Grade 3+ AE 15 (11%) 37 (11%)

2 years SOC+DocP SOC+AAP

Patients in safety dataset 104 271

Grade 3+ AE 11 (11%) 30 (11%)

Adverse events – prevalence at 1 year and 2 years

Safety dataset includes patients who::: started treatment:: with assessment in toxicity window :: without FFS event before window


Wallis, Eur Urol, 2017

6067 patients included (1921 events)

- 1181 (19.5%) Docetaxel + ADT (391 events)

- 1557 (25.7%) Abiraterone +ADT (353 events)

- 3329 (54.9%) ADT alone (1177 events)

Docetaxel +ADT vs ADT

Pooled HR for OS

HR 0.75 (95%CI 0.55-0.72)

Abiraterone + ADT vs ADT

Pooled HR for OS

HR 0.75 (95%CI 0.55-0.72)

Indirect comparision of Abi + ADT vs Docetaxel + ADT shows no significant difference on OS

Choice of Abiraterone or Docetaxel may be driven by factors beyond survival outcomes:

- Treatment-associated side effects

- Physician – patient preferences

- Availability

- Cost

Documents

Current role of chemotherapy in hormone-naïve patients · 2017. 11. 9. · M1 HSPC Stratification-Low vs High volume-Age 70 yrs-MAB 30 days-SER prevention-Adjuvant