Optimizing prostate cancer therapy strategies 5th ESO-ESMO … · Disclosures –Eleni Efstathiou Research Support/P.I. Janssen, Sanofi-Genzyme, Astellas/Medivation, Innocrin, Tracon

Optimizing prostate cancer therapy strategies

Where do we stand in 2019

Eleni Efstathiou M.D., PhD.

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Disclosures – Eleni EfstathiouResearch Support/P.I.

Janssen, Sanofi-Genzyme, Astellas/Medivation, Innocrin,

Tracon

Employee NA

Consultant NA

Major Stockholder NA

Speakers Bureau NA

Honoraria Janssen, Sanofi-Genzyme,

Scientific Advisory BoardJanssen, Sanofi-Genzyme, Tolmar, Takeda, Astra Zeneca,

Bayer,

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“Novel”

Androgen signaling

inhibitionBone Targeting AgentsChemotherapy

Approved ‘systemic’ therapies by biologic domain in advanced Prostate Cancer

Immunotherapy

Abiraterone AcetateEnzalutamideApalutamide Daralutamide

DocetaxelCabazitaxel Sipuleucel T Radium-223

Treatment of Primary

A systemic therapy after all? 5t

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Is there a change in therapeutic landscape?

Approved Agents moved upfront

mCRPC, metastatic castration-resistant prostate cancer;

mHSPC, metastatic hormone-sensitive prostate cancer;

nmCRPC, non-metastatic castration-resistant prostate cancer.

Hong JH, Kim IY. Korean J Urol. 2014;55:153-60.

Mottet N, et al. EAU/ESTRO/ESUR/SIOG Guidelines on Prostate Cancer 2017.

Available from: http://uroweb.org/guideline/prostate-cancer. Accessed February 2018.

Adapted from: Scher HI, et al. J Clin Oncol. 2016;34:1402-18.

Localised or locally

advanced prostate

cancer

Biochemical

recurrence

nmCRPC

Primary progressive

mHSPC

Newly diagnosed

mHSPC

mCRPCTerminal disease

(death)

First prostate cancer diagnosis

Non-metastatic

Metastatic castration resistant

Metastatic hormone sensitive

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Is Earlier Treatment Better ?

Sure … but what is the target ?

In majority of cases the Androgen Signaling Axis

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Enriched Genomic Alteration landscape in far advanced disease too late for Androgen

signaling inhibition and in the bigger picture for most targeting agents

Robinson D, et al. Cell. 2015;162:454

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Localised Disease: “limited” mutational landscape

TCGA Cell 2015

Would targeting earlier limit the variables and resistance ?

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Increase in mutation frequency and copy number alteration associated with

more advanced stage: in other words choose wisely ..?

Abida et al JCO Precision Oncology 2018 5t

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Tackling newly diagnosed metastatic prostate cancer









advanced prostate

cancer

Biochemical

recurrence

nmCRPC

Primary progressive

mHSPC

Newly diagnosed

mHSPC


(death)


Non-metastatic



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ADT + Docetaxel Overall Survival benefit in mHNPC

HR, hazard ratio.

1. Gravis G, et al. Eur Urol. 2016;70:256-62.

2. Kyriakopoulos CE, et al. J Clin Oncol. 2018;36:1080-7.

GETUG AFU-151 CHAARTED2

OS

(p

rop

ort

ion

)

1.0

0.8

0.4

0.2

0

0.6

0.9

0.7

0.3

0.1

0.5

Follow-up (years)

1 2 3 4 60 5 87

175

171

145

148

119

116

102

94

72

61

192

193

87

76

32

33

No. of patients at risk:

ADT + Doc

ADT alone

Median OS (months)

ADT: 48.6 (40.9–60.6)

ADT + Doc: 62.1 (49.5–73.7)

HR (95% CI): 0.88 (0.68–1.14);

p = 0.3

ADT + Doc

ADT alone

366

352

314

278

245

198

155

126

28

21

397

393

67

45

7

2

2

0

0

0

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Attempt 3 : STAMPEDE

James et al Lancet 2015

Patient Population mHNPC or HNPC N+Localized high risk PCawith plan to radiate

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STAMPEDE ADT + Docetaxel Survival benefit in mHNPC

James ND, et al. Lancet. 2016;387:1163-77.

1.0

0.8

0.4

0.2

0

0.6

OS

(%

)

Time from randomisation (months)

12 24 36 48 720 60

SOC

SOC + Doc

STAMPEDE: M1 disease

362 326 250 155 91 38 25

724 646 474 262 137 60 26

STAMPEDE: all patients

SOC, standard of care.

100

80

40

20

0

60

OS

(%

)

12 24 36 48 720 60 84

1093

545

876

447

538

290

322

181

87

51

1,184

592

166

93

43

20

(73)

(33)

(134)

(52)

(92)

(35)

(60)

(22)

(17)

(13)

(35)

(12)

(2)

(6)

SOC by Kaplan-Meier

SOC by flexible parametric model

SOC + Doc by Kaplan-Meier

SOC + Doc by flexible parametric model

No. of patients at risk (events)

SOC + Doc

SOC


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Is ADT + Doc effective in “low-volume” mHNPC?

Kyriakopoulos CE, et al. J Clin Oncol. 2018;36:1080-7.

Kaplan-Meier estimates of OS for total patient population.

NR, not reached.

High-volume mHSPC Low-volume mHSPC

A uniform effect was noted for ADT + Doc in the STAMPEDE study

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ADT + Abiraterone Overall Survival benefit in mHNPC

1. Fizazi K, et al. N Engl J Med. 2017;377:352-60.

2. James ND, et al. N Engl J Med. 2017;377:338-51.CI, confidence interval; mHSPC, metastatic hormone-sensitive prostate cancer; OS, overall survival.

STAMPEDE2LATITUDE1

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Chi et al ASCO GU 2019

LATITUDE Final Analysis: Overall Survival

(median follow up 52 months)

• Median OS for patients receiving ADT + AA+P reached 4.5 years, 16.8 months longer than ADT+ placebos

0 6 12 18 24 30 36 42 48 54 60 66

Months

0

20

40

60

80

100

Ove

rall

su

rviv

al (%

)ADT + AA + P, 53.3 mo

ADT + placebos, 36.5 moNo. of events:

ADT + AA + P: 275 (46%)

ADT + placebos: 343 (57%)

HR 0.66 (95% CI: 0.560.78)

P<0.0001

Median treatment exposure:

ADT + AA + P: 25.8 mo

ADT + placebos: 14.4 mo

597 565 529 479 425 389 351 311 240 124 40 0

602 564 505 432 368 315 256 220 165 69 23 0

No. at risk

ADT + AA + P

ADT + placebos

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HOW DID PATIENTS FARE BASED ON RISK AND VOLUME IN

STAMPEDE ( ABIRATERONE+ADT VS ADT)

Pt No Median F/U

(mo)

HR

LATITUDE M1

“high risk”

1199 30.4 0.62 (0.51-0.76)

STAMPEDE AAP

M0+M1

1917 40 0.63 (0.52-0.76)

STAMPEDE AAP

(M1)

1002 40 0.61 (0.49-0.75)

STAMPEDE AAP

(M0)

915 40 0.75 (0.48-1.18)

Definition

CHAARTED

(volume)

High Visceral metastases

AND/OR

≥4 Bone metastasis

(≥1 outside vertebral column or spine)

LATITUDE

(risk)

High ≥2 high risk features

• ≥3 Bone metastasis

• Visceral metastasis

• ≥Gleason 8

What do we mean by ”Risk” or “Volume?”

Parker et al ESMO 2018 5t

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Population Number %

LATITUDE Low 428 47.5

LATITUDE High 473 52.5

CHAARTED Low 402 44.6

CHAARTED High 499 55.4

Individual CHAARTED Low

CHAARTED High

LATITUDE Low 333 (37%) 95 (10.5%)

LATITUDE High 69 (7.7) 404 (44.8)

STAMPEDE (ABIRATERONE / ADT )

SUBGROUP RISK/VOLUME DISTRIBUTION

N:942

18.2% NON OVERLAPPING

Parker et al ESMO 2018 5t

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RESULTS: LATITUDE RISK STRATIFICATION

EQUIVALENT PERFORMANCE

ADT + Abiraterone + Prednisolone (AAP) ADT alone Parker et al ESMO 2018 5t

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CHAARTED VOLUME CRITERIA: EQUIVALENT PERFORMANCE

ADT + Abiraterone + Prednisolone (AAP) better

ADT alone better Parker et al ESMO 2018

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Both treatment options show improvements in HRQoL over ADT

alone

1. Chi KN, et al. Lancet Oncol. 2018:19;194-206.

2. Patrick-Miller L, et al. J Clin Oncol. 2016;34:(Suppl 2S): abstract 286. FACT-P, Functional Assessment of Cancer Therapy–Prostate; HRQoL, health-related quality of life.

LATITUDE

ADT vs ADT + AAP1

CHAARTED

ADT vs ADT + Doc2

120

118

116

114

FA

CT

-P t

ota

l

3 60 9 12

Time (months)

ADT +

AAPADT

ADT +

AAPADT

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AEs: grade 3–5, n (%)ADT

(n = 1,184)

ADT + Doc

(n = 592)

Any 所有 399 (32) 288 (52)

Febrile neutropenia

发热性中性粒细胞减少15 (1) 84 (15)

Neutropenia

中性粒细胞减少6 (< 1) 66 (12)

GI disorders 消化道反应 36 (3) 45 (8)

Respiratory disorders

呼吸系统疾病27 (2) 29 (5)

Adverse Events between Abiraterone and Docetaxel

AEs: grade 3–5, n (%)ADT

(n = 960)

ADT + AAP

(n = 948)

Any 所有 315 (33) 443 (47)

Cardiovascular disorders 心血管疾病 41 (4) 92 (10)

Hypertension 高血压 13 (1) 44 (5)

Cardiac dysrhythmia 心律失常 2 (< 1) 14 (1)

Hepatic disorders 肝脏疾病 12 (1) 70 (7)

Increased ALT level ALT升高 4 (< 1) 53 (6)

Respiratory disorders 呼吸系统疾病 23 (2) 44 (5)

Laboratory abnormalities 实验室指标异常 21 (2) 34 (4)

STAMPEDE

ADT vs ADT + AAP1

STAMPEDE

ADT vs ADT + Doc2

1. James ND, et al. N Engl J Med. 2017;377:338-51.

2. James ND, et al. Lancet. 2016;387:1163-77.

aOnly AEs that differ by > 2% in the STAMPEDE trial (AAP and Doc arms) are shown.

AE, adverse event; ALT, alanine transaminase; GI, gastrointestinal.

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Strong evidence favouring AA+P

Toxicity profiles quite different and well known

Weak evidence favouring AA+P

No good evidence of a difference

FavoursADT+AA+P

FavoursADT+DOC

Hazard ratio

Metastatic progression-free

survival

Progression-free survival

Failure-free survival

Symptomatic skeletal events

Cause-specific survival

Overall survival

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

Proportionately different time spent in each disease state

No Difference in Survival in HNPC with use of Docetaxel or Abiraterone

AA+P = abiraterone acetate plus prednisone/prednisolone; ADT = androgen-deprivation therapy; DOC = docetaxel

Adapted from: Sydes M, et al. Abstract LBA31 presented at ESMO 2017Sydes et al Annals of Oncology 20185t

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STAMPEDE Subsequent Treatments:

Frequent use of Docetaxel post AA

limited use of drugs on ADT arm

James et al NEJM 20175th

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Sequencing and Accessing

Is it then matter of sequence or equally so of access ?

Availability

“window of opportunity”

Patient vulnerability / frailty

To what extent can biology guide us in determining sequence a priori ?

Making the most of heterogeneity / classification

Overlapping activity ?

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Would there be a preference of docetaxel over abiraterone ?

Docetaxel Preference

Low cost – Shorter duration

Disease that has aggressive features

High volume disease and specifically visceral disease?

Young men (early 50s) regardless of volume of disease ?

Window of concern in cases with constitutional symptomatology ?

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NCCN: “CAB provides modest to no benefit over castration alone in patients with

metastatic disease.”

ASCO: Antiandrogens (eg, bicalutamide, flutamide, nilutamide) may be offered,

accompanied by discussion of limited known clinical benefit”

EAU: ”CAB using non-steroidal anti-androgen (NSAA) appears to provide a small

survival advantage (<5%) vs. monotherapy (surgical castration or LHRH agonists)

beyond 5 years. However, some of the larger trials included in these reviews were

methodologically flawed and it is unlikely that this small advantage, if any, is useful in

daily clinical practice.”

NICE:” Do not offer CAB as a first line treatment for men with metastatic prostate

cancer”

Combined Androgen Blockade (CAB) in mHNPC

NCCN guidelines version3, 2016Basch et al. J. Clin. Oncol. 2014 32(30): 3436-3448https://pathways.nice.org.uk/ Mottet N, et al. EAU guidelines. https://uroweb.org/guideline/prostate-cancer/. Accessed June 13, 20165t

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Phase II evidence with older compounds only PSA response

PSA > 50%

Bicalutamide addition/withdrawal 15 - 33%1

Antiandrogen change 24 %2

Estramustinphosphate 20 %

Aminogluthetimid (+HC) 49 %3

Ketokonazole (+HC) 62 %4

Estrogens 80 %5

1Small, JCO 1997; 2Scher, JCO 1997; 3Sartor JNCI 1994;4Small, J Urol 1997, 5Orlando Ann Oncol 2000

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ARE THERE MEN WHO ARE BETTER OFF WITH ADT ALONE

Maybe Older men ? DATA FAVOR ABIRATERONE

SIOG analyses reveal that geriatric patients have more aggressive disease

They should be treated based on the presence of comorbidities :

hence the only clear contraindication is heart failure

Maybe older men with low metastatic volume : AGAIN DATA FAVOR ABIRATERONE

This analysis supports use of Abiraterone in low metastatic volume

Importantly significant early on impact Skeletal related events !

(Extrapolate better QOL)

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IS THE ADDITION OF ABIRATERONE TO ADT DETRIMENTAL ?

1 ADT alone causes known Adverse events that are sometimes overlooked including :

Short Term : Arterial hypertension, Metabolic Syndrome exacerbation ( weight gain, diabetes/ prediabetes,

hyperlipidemia), Emotional, AST/ ALT elevation, Hot flashes, fatigue.

Mid/ long term : bone loss, sarcopenia, cognitive decline ( mainly memory in subset)

Abiraterone Addition – may increase frequency and severity of events

Only added clinical risk :Hypokalemia ( a lot of older men on diuretics)

2 Only clear contraindication is Heart failure with low EF

3 Familiarity with Abiraterone has the risk of reduced monitoring

Conclusion : Patients on any hormonal manipulation need monitoring and good internal medicine support

Addition of Abiraterone does not significantly exacerbate events

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Time since registration(months)

Pro

babi

lity

of P

SA

-rel

apse

free

0.0

0.2

0.4

0.6

0.8

1.0

0 12 24 36 48

LHRH alone (70/98)LHRH+AA+Pred (58/99)

p-value=0.007

Efforts Underway: Intermittent Advanced

Androgen Signaling inhibition in M0 HNPC

Hazard Ratio 0.62(95% CI 0.44-0.88)

Efstathiou et al ASCO 2018

Link “driver biology” to outcomes by characterizing primary cancers

Extend findings to propose a risk stratified, marker based, adjuvant therapy in men at risk for recurrence following surgery

No diffencein time to eugonad state

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Residual Tumor following neoadjuvant abiraterone

for high risk prostate cancer AA+LHRHa LHRHa

Tumor Cell Density (%)

P < 0.0001 P < 0.0001

Tumor Epithelium Volume: Tumor Cell Density × Volume Tumor Volume (cc)

5

4

3

2

1

0

80

60

40

20

0

6

4

2

0

P = 0.003

Tumor Quantification measures associates with biochemical recurrence ( p < 0.001)superior to association of pathology stage with outcome (p< 0.001)

Efstathiou et al Eur Urol 2019 in Press5t

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How can data on EBRT on low volume disease change our practice with regard to abiraterone ?

MAYBE A COMBINATORIAL STRATEGY OPPORTUNITY

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MRC CTU at UCL

STAMPEDE: Radiotherapy to the primary in newly diagnosed mHNPC

Though not positive for unselected patients Clearly positive for the prespecified subset analysis of

Low metastatic burden

Aka a treatment with bone scan as a ‘predictor’ of outcome

Parker et al Lancet 20185t

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Overall survival: exploratory consistency analyses by baseline features

Is docetaxel planned as part of SOC?

Gleason sum score

Nodal status

Tumour status

WHO PS 0 vs 1-2

Age at randomisation

Subgroup

Overall

Docetaxel

No docetaxel

8-10

<=7

N+

N0

T4

T3

T2

<T2

1-2

0

70 or over

Under 70

Dths/N

SOC-only

34/182

357/844

332/818

41/173

251/617

118/345

126/260

200/583

33/84

5/12

120/297

271/729

168/433

223/593

Dths/N

SOC+RT

28/182

342/847

303/807

54/172

228/618

116/343

104/246

201/600

33/89

5/14

118/297

252/732

142/435

228/594

p-value

Interaction

0.63

0.084

0.47

0.66

0.87

0.066

(95% CI)

Haz. Ratio

0.92 (0.80, 1.06)

0.81 (0.49, 1.34)

0.93 (0.80, 1.08)

0.91 (0.78, 1.06)

1.34 (0.89, 2.02)

0.87 (0.72, 1.04)

0.97 (0.75, 1.25)

0.78 (0.60, 1.02)

0.97 (0.80, 1.18)

0.75 (0.44, 1.27)

0.61 (0.13, 2.82)

0.94 (0.73, 1.21)

0.92 (0.77, 1.09)

0.78 (0.63, 0.98)

1.03 (0.86, 1.24)

Favours: SOC+RT SOC-only

.5 .6 .7 .8 .9 1 1.2 1.4

SOC vs SOC+RT

No data on combination

With AA

However Synergy

anticipated

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Confirmation of tissue based driven observations

Bova et al Nature 20165th

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Will anticipated data

impact tailoring treatment

to the patient

even further?

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Triplet vs doublet treatment

BIC, bicalutamide; ENZA, enzalutamide; rPFS, radiographic PFS; SWOG, Southwest Oncology Group.

Study Identifier Arms Patients (N)Primary

endpoint

Status

LATITUDE NCT01715285 ADT ± AA 1,209 rPFS, OS Ongoing

STAMPEDE (Arm G) NCT00268476 ADT ± AA 1,800 OS Ongoing

PEACE-1 NCT01957436

ADT ± Doc vsADT + AA ± Doc

(± local RT)916 PFS, OS Recruiting

STAMPEDE (Arm J) NCT00268476 ADT ± AA + ENZA 1,800 OS Ongoing

SWOG-1216 NCT01809691 ADT + TAK-700 vs

ADT + BIC 1,304 OS Recruiting

ENZAMET NCT02446405 ADT + ENZA vs

ADT + antiandrogen1,100 OS Ongoing

TITAN NCT02489318 ADT ± APA 1,000 rPFS, OS Ongoing

ARCHES NCT02677896 ADT ± ENZA 1,100 rPFS Ongoing

ARASENS NCT02799602 ADT + Doc ± ODM-201 1,300 OS Ongoing

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Therapy development in prostate cancer

Earlier treatment merits and risks

Biology of disease Cumulative Adverse Events

Optimizing therapeutic strategies : short / mid /long-term treatment continuum

Novel targets and drug development how can / when will it affect patient care ?

The multifactorial role of the ‘host’

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When did nmCRPC become a “hot topic”









advanced prostate

cancer

Biochemical

recurrence

nmCRPC

Primary progressive

mHSPC

Newly diagnosed

mHSPC


(death)


Non-metastatic



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Definition of CRPC

Mottet N, et al. EAU/ESTRO/ESUR/SIOG Guidelines on Prostate Cancer 2018. Available

from: http://uroweb.org/guideline/prostate-cancer. Accessed February 2019.

Castrate serum testosterone <50 ng/dL or 1.7

nmol/L

AND EITHER

Biochemical progression

3 consecutive rises of PSA

with PSA >2 ng/mL

Radiological progression

Appearance of ≥2 bone

lesions on bone scan or

enlargement of soft tissue

lesion

(RECIST criteria)

OR

Based on conventional bone scan and CT Scan

Trivia question:

Which country approved novel androgen signalling inhibitors for all CRPC as a first indication? 5t

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1. Moreira DM, et al. Urology. 2016;96:171-6.

2. Smith MR, et al. J Clin Oncol. 2005;23:2918-25. 3. Smith MR, et al. Cancer. 2011;117:2077-85.

4. Freedland SJ, et al. J Clin Oncol. 2007;25:1765-71. 5. Smith MR, et al. J Clin Oncol. 2013;31:3800-6.

nmCRPC, non-metastatic castration-resistant prostate cancer;

PSADT, prostate specific antigen doubling time.

PSADT as a measure of progression in the

nmCRPC

• Patients with M0 CRPC will invariably

develop detectable metastases

• Rapidly rising PSA in these patients is

linked to risk of:1-4

Metastasis

Locoregional disease progression

and symptom development

Morbidity

Limited survival

PSADT (months)

Re

lati

ve r

isk

for

bo

ne

m

eta

stas

is o

r d

eat

h

Shorter PSADT

Inc

rea

sin

g r

isk

20 18 16 14 12 10 8 6 4 2

3.0

2.8

2.6

2.4

2.2

2.0

1.8

1.6

1.4

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Androgen signaling inhibition in nmCRPC:

Does it work ?

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.

3. Fizazi K, et al. N Engl J Med. 2019;doi: 10.1056/NEJMoa1815761

Apalutamide Enzalutamide Darolutamide

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Trial Design: All basically identical

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.

3. Fizazi K, et al. N Engl J Med. 2019;doi: 10.1056/NEJMoa1815761

Eligibility• nmCRPC

• PSADT ≤ 10 months

• Baseline PSA ≥ 2 ng/L

On-study requirement• Continuous ADT

Stratification• PSADT < 6 or 6–10 months

• Bone-targeted agent use: yes/no

Treatment + ADT

PBO + ADT

2:1

Primary endpoint:

Metastases Free Survival (MFS)

Key Secondary endpoints:

Overall Survival, Time to PSA

Progression, Quality of Life

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NCT01946204PSADT, prostate-specific antigen doubling time; ADT, androgen deprivation therapy; APA, apalutamide; QD, daily; PBO, placebo; MFS, metastasis-free survival; Rx, treatment; MD, medical doctor; ABI/PRED, abiraterone acetate plus prednisone; PFS2, second progression-free survival.

Eligibility• nmCRPC

- Pelvic nodes <2 cm below iliac bifurcation (N1) allowed

• PSADT ≤10 months

On-Study Requirement• Continuous ADT

Stratifications• PSADT >6 mo or ≤6 mo• Bone-sparing agents, y/n• N0 or N1

Second Rx at MD’s

discretion, including

open-label ABI/PRED

APA 240 mg QD

+ ADT(n = 806)

PBO +

ADT(n = 401)

Randomization

MFS

PROGRESSION

2nd progression-free survival

(PFS2)

MFS(primary end point)

Ongoing PBO patients crossover to APA after unblinding

2:1(N = 1,207)

SPARTAN ─ Overall Study Design Phase 3 Placebo-controlled, Randomized International Study

45

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MFS PBO APA

Median time to event, mo 16.2 40.5

HR, 0.28 (95% CI, 0.23-0.35),

P value <0.0001

Time to Symptomatic Progression PBO APA

Median time to event, mo Not reached Not reached

HR, 0.45 (95% CI, 0.32-0.63),

P value <0.0001

Time to PSA Progression PBO APA

Median time to event, mo 3.7 Not reached

HR, 0.06 (95% CI, 0.05-0.08),

P value <0.0001

APAPBO

APA

PBO

806

0

20

40

60

80

100

Meta

sta

sis

-free S

urviv

al (%

)

MonthsNo. at risk

713 652 514 398 282 180 96 36 16 3 0

401 291 220 153 91 58 34 13 5 1 0 0

0 4 8 12 16 2420 28 32 36 40 44

Primary End Point:MFS72% risk reduction of distant progression or death

PSA, prostate-specific antigen; HR, hazard ratio; CI, confidence interval; SRE, skeletal-related event; sx, symptoms.

Secondary End Point:Time to Symptomatic Progression55% risk reduction of SRE pain progression/worsening sx, clinically significant sx requiring intervention

APA

PBO

0 4 8 12 16 20 24 28 32 36 40 44

806 769 732 601 478 344 226 127 49 19 4 0

401 373 344 270 206 152 96 45 17 7 0 0

Pati

en

ts W

ith

ou

t S

ym

pto

mati

c P

rog

ressio

n (

%)

0

20

40

60

80

100

Months

APA

PBO

No. at risk

Exploratory End Point:Time to PSA Progression94% risk reduction in PSA progression

APAPBO

806 695 597 435 306 215 128 69 29 2 0

401 139 50 14 8 4 0 0 0 0 0 0

11

Pati

en

ts W

ith

ou

t P

SA

Prog

ressio

n (

%)

0

20

40

60

80

100

0 4 8 12 16 20 24 28 32 36 40 44

Months

APA

PBO

No. at risk

SPARTAN Results: APA Significantly Prolonged MFS, Time to Symptomatic

Progression, and Time to PSA Progression

46

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47

Objective• Report the updated SPARTAN PFS2 exploratory end point and safety data after 1 year of

additional follow-up using cumulative data.

• PFS2 is defined as the time from randomization to disease progression on subsequent

anticancer therapy, or death.All men on placebo

Were given

apalutamide

or abiraterone

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Median time to PFS2 was not reached (APA) versus 39.3 months (PBO)

50% reduction in the risk of disease progression over two lines of anticancer therapy or death in favor of APA

Pa

tie

nts

Wit

ho

ut

Se

co

nd

ary

Pro

gre

ss

ion

or

Dea

th

Time From Randomization (Months)

0 4 528 12 16 20 24 28 32 36 40 44 48

HR, 0.5 (95% CI, 0.39-0.63)

P <0.0001

100

80

60

40

20

0

806 779 760 730 693 637 525 398 289 191 117 44 13 0

401 386 362 331 285 243 182 124 75 45 26 9 1 0

No. at risk

APA

PBO

PBO, 39.3 mo

(median)

APA, not reached

Apalutamide Shows Continued Benefit on PFS2

48

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Why is mCRPC lagging behind these past few years ?









advanced prostate

cancer

Biochemical

recurrence

nmCRPC

Primary progressive

mHSPC

Newly diagnosed

mHSPC


(death)


Non-metastatic



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Advancement in mCRPC

1. Fizazi K, et al. N Engl J Med. 2017;377:352-60. 2. Sweeney CJ et al. N Engl J Med. 2015; 373:737-46.

3 Tannock IF, et al. N Engl J Med. 2004;351:1502-12. 4. Ryan CJ, et al. The Lancet. 2015;16:152-60. 6.

Beer TM, et al. N Engl J Med. 2014;371:424-33. 7. Scher HI et al. N Engl J Med 2012;367:1187-97. 8. de

Bono J, et al. Lancet. 2010;376:1147-54. 9. Parker C et al. Engl J Med 2013;369:213-23.

Study Agents N Indication HR ∆OS (mo)

TAX-3273 DOC/P vs

mitoxantrone /P1,006 mCRPC, symptomatic or not 0.76 +2.9

COU-AA-3024

ABI/P vs P 1,088mCRPC (pre-DOC), mild/no symptoms

No visceral mets0.81 +4.4

COU-AA-3015

ABI/P vs P 1,195 mCRPC (post-DOC) 0.74 +4.6

PREVAIL6

ENZ vs pbo 1,717 mCRPC (pre-DOC), mild/no symptoms 0.77 +4.0

AFFIRM7

ENZ vs pbo (or P) 1,199 mCRPC (post-DOC) 0.63 +4.8

TROPIC8 CABA/P vs mito/P 755 mCRPC (post-DOC) 0.70 +2.4

ALSYMPCA9 Radium-223 vs pbo 921 mCRPC (post-DOC or unfit for DOC) 0.70 +2.8

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Determines the efficacy of individual therapeutic

agents and thus leads to drug approval However

It does not inform impactful sequences or combinations

and strategy for their allocation over time to maximize

benefits !

“Drug Development Paradigm”

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Challenges

Patients treated on reported phase III randomized studies are

selected by “crude” prognostic criteria.

Patients treated as “one size fits all” ;

therefore selection of therapy by objective criteria or predictors

not enabled

The design of “practice changing” studies does not account

for interaction between “therapy domains”;

Thus sequences become empirical and combinations a concern.

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Time for Combinatorial Strategy ?

Still far removed from selecting specific tumor subsets

And focused on a one fits all approach

-We should keep in mind the negative track record

( ~15 negative docetaxel plus trials )

Enticing but with a lot of caveats if untested

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Chemo Based Combinatorial Trials

Quinn et al Annals of Onc 2018

And then there are the novel androgen

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HERE’S HOW WE CAN EASILY FAIL:

ERA 223 (NCT02043678)

Bone health agents (denosumab or bisphosphonates) only permitted in patients receiving them at baseline; initiation during the study prohibited to prevent confounding effects.ALP, alkaline phosphatase; CRPC, castration-resistant prostate cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; HRQoL, health-related quality of life; IV, intravenous; mCRPC, metastatic castration-resistant prostate cancer; OS, overall survival; PSA, prostate-specific antigen; rPFS, radiological progression-free survival; SSE-FS, symptomatic skeletal event-free survival.

Target

accrual

N=800Study population

• Patients with bone-predominant

mCRPC (≥2 bone metastases)

• Asymptomatic or mildly symptomatic

• ECOG PS of 0 or 1

• No prior chemotherapy for CRPC

• No known brain or visceral

metastases

1:1

Randomisation

Primary endpoint• SSE-FS

Secondary endpoints• OS

• rPFS

• Time to chemotherapy

• Time to opiate use for cancer

pain

• Safety

Exploratory endpoints• PSA response

• Time to PSA progression

• ALP response

• Time to ALP progression

• HRQoL

Abiraterone acetate 1000 mg qd and prednisone/prednisolone 5 mg bid (AAP) +

Radium-223 55 kBq/kg IV every 4 weeks for 6 cycles

Abiraterone acetate 1000 mg qd and prednisone/prednisolone 5 mg bid (AAP) +

Matching placebo

Stratification factors

• Geographical region

• Total ALP level at baseline (ALP <90 vs ≥90 U/L)

• Use of bone health agents

389 events were required to detect a 39%

increase in SSE-FS using a test with a 2-sided

alpha of 0.05, 90% power and 1:1 randomisation

Accrual dates 3/2014 – 8/2016

Smith et al ESMO 20185th

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Primary Endpoint not met …

SSE-FS

AAP +

radium-223

N=401

AAP +

placebo

N=405

Events, n (%) 196 (49) 190 (47)

Median (95% CI),

months

22.3

(20.4–24.8)

26.0

(21.8–28.3)

HR (95% CI) 1.122 (0.917–1.374)

P-value (2-sided) 0.2636

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

401 380 355 310 272 245 202 126 78 44 25 12 7 6 1 0405 384 353 323 301 274 214 152 94 59 30 16 6 5 3 0

Number at risk

Sym

pto

matic S

kele

tal E

vent-

Fre

e S

urv

ival P

robabili

ty

AAP + radium-223AAP + placebo

Months Since Randomisation

TEAEs in ≥15% of patients in either group, n (%)AAP + radium-223

N=392

AAP + placebo

N=394

All Grade 3 Grade 4 All Grade 3 Grade 4

Fracture† 103 (26) 35 (9) 1 (0.3) 38 (10)* 12 (3) 0

Fracture Rate more than doubles with the combination


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Post-Hoc Subgroup Analysis of Fractures by Baseline

Bone Health Agent Use

AAP, abiraterone acetate and prednisone/prednisolone; BHA, bone health agent; NE, not estimable.

Patients with

≥1 fracture (%)

29

15

37

11

7

15

0

5

10

15

20

25

30

35

40

Overall population Patients with BHAs at baseline Patients without BHAs at baseline

AAP + placebo

AAP + radium-223


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Will PARP inhibitors change the landscape?

It all depends on the approach

Drug ClinicalTrials.gov ID Phase Primary endpoint

mCRPC (Phase 1/2)

Olaparib NCT01682772

NCT03263650

NCT01972217

NCT02893917

NCT03317392

NCT03012321

2

2 randomised

2 randomised

2 randomised

1/2 randomised

2 randomised

RR

PFS

rPFS

rPFS

(Phase 2) rPFS

PFS

Niraparib NCT02854436 2 ORR

Rucaparib NCT02952534

NCT03338790

2

2 randomised

ORR + PSA response

ORR + PSA response

Talazoparib NCT03148795 2 ORR

Veliparib NCT0157612 2 randomised PSA response


mHSPC

Olaparib NCT03047135 2 PSA response

Rucaparib NCT03413995 2 PSA response


mCRPC (Phase 3)

Olaparib NCT03263650 3 rPFS

Rucaparib NCT02975934 3 rPFS

Talazoparib NCT03395197 3 rPFS

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*Prednisone/prednisolone (5 mg) was administered alongside abiraterone as indicated. bid, twice daily; CTC, circulating tumor cell; HRRm, homologous recombination

repair gene mutation; mCRPC, metastatic castration-resistant prostate cancer; od, once daily; PCWG, Prostate Cancer Working Group; RECIST, Response Evaluation

Criteria in Solid Tumors; rPFS, radiographic progression-free survival

• mCRPC

• Prior treatment with

docetaxel for mCRPC

• ≤2 prior lines of

chemotherapy

• No prior 2nd-generation

antihormonal agents

Randomized 1:1

Double-blind

N~140

Olaparib tablets

300 mg bid

+

abiraterone*

1000 mg od

Placebo

+

abiraterone*

1000 mg od

Secondary endpoints:

• rPFS by HRRm status

• Time to second progression (PFS2)

• Overall survival (OS)

• Objective response rate (ORR)

• CTC-conversion rate

• Safety and tolerability

• Times to first and second subsequent

therapies (TFST/TSST)

• Health-related quality of life (HRQoL)

Primary endpoint:

• Radiologic progression-free survival

(investigator-assessed; RECIST 1.1, PCWG2)

Tre

atm

en

t u

ntil d

ise

ase

pro

gre

ssio

n

A Randomized Phase II Trial: Olaparib Combined With Abiraterone in

Patients With Metastatic Castration-Resistant Prostate Cancer

Clarke N, et al. Lancet Oncology 2018.5t

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Combinatorial Strategy report

Outcome independent of mutation status

0 3 6 9 12 15 18 21 24 27 30

1.0

0.8

0.6

0.4

0.2

0.0

Pro

po

rtio

n o

f p

ati

en

ts e

ve

nt-

fre

e

= 5.6


Events, n (%)

K-M median, monthsOlaparib + AAP

(n = 71)

AAP

(n = 71)

46 (65)

13.8

54 (76)

8.2

HR 0.65

95% CI 0.44–0.97; p = 0.034

No. of patients at risk

Olaparib + AAP 71 58 50 42 33 26 21 18 13 8 0

AAP 71 48 39 25 21 19 16 14 10 7 0


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OLA + AAP: Safety is a very important consideration

Olaparib + AAP (n = 71) AAP (n = 71)

Nausea 27 15

Anaemia 22 1

Back pain 18 14

Constipation 18 8

Asthenia 16 10

Fatigue 15 9

Vomiting 15 9

Peripheral oedema 13 8

Decreased appetite 12 5

Diarrhoea 11 8

Cough 11 2

Serious cardiovascular AEs 7 1

Olaparib + AAP

Myocardial infarction, n = 4; fatal cardiac failure, n = 1;

chronic cardiac failure, n = 1; fatal ischaemic stroke, n = 1

AAP

Thrombotic stroke, n = 1

All grades

Grade ≥ 3

2

15

1

1

3

1

2

2

7

2

1

1

1

1


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Newly diagnosed

mHSPC

The Disease landscape and Therapy Development








High risk Localised

prostate cancerBiochemical

recurrence

nmCRPC

Primary

progressive

mHSPC

mCRPCEnd Stage

disease

Intermediate Risk

prostate cancer

Unmet Need

Currently Addressed

Primary field of drug

development


Non-metastatic



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Making the most of data

Our clinical decisions do not fit a ‘linear model’ and are the result of

‘multivariate’ considerations informed by details

It s tougher to treat patients outside trials

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Trying to be “Precise” in daily practice (2015)（2015）

80 yr old veteran ‘full of life’

Reached MDACC with a PSA of 8500 in a wheelchair with pending spinal cord compression

and weight loss, anemia, high ldh (PS:3)

Biopsy – GS 8 (4+4)

Started 240mg degarelix loading dose and lower T spine radiation (+steroids)

Improved to PS 1 and transitioned to LHRHa in 4 weeks

WHAT WOULD YOU CONSIDER ADDING ?

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How Would you treat gentleman ?

A. Add Docetaxel

B.Add Abiraterone Acetate

C.Add Bicalutamide

D.Continue Monitoring

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Primary Resistance to ADT within 3 months

8500

1800

3900

PS 2Diabetic Vascular disease lack of local social/ family support

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How would you treat gentleman ?

A. Add Docetaxel

B Add Abiraterone Acetate

C Add Bicalutamide

D Perform Imaging first

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Diagnosis Bone Scan (3/2015)

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Follow up Bone Scan (08/2015)

ALP had normalised and pain improved 5t

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Lymph node Disease Development

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How Would you treat gentleman ?

A. Add Docetaxel

B Add Abiraterone Acetate

C Add Bicalutamide

D Continue Monitoring

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Sustained Biochemical and Clinical Response

on Abiraterone Acetate

ADT initiation

ABI initiation PSA 3900

PSA 19PSA 3

Improvement PS 1 No need for opiatesPatient remains on treatment to Date

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Alkaline Phosphatase Kinetics

Do not be disturbed by Transient ALP elevation

ADT

ABI

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The 2019 Dilemma

A patient like Bruce if diagnosed today would have been

treated with abiraterone acetate +LHRHa in a US practice

… the question for all of us is :

What if Bruce was fit for both docetaxel and abiraterone ?

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Biomarker Driven Research for prime time?

Not so fast ..

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Hypothesis:

Integration biologic

understanding with clinical

context can lead to successful

treatment strategy.

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Paul: 82 yr old very fit and active, BMI 24

Urination frequency and unexplained loss of weight 10 kg in 2 ms .

No Pain

June 15 PSA 2.2– June 16 PSA 25

July 16 Mayo Clinic : de novo metastatic PCa GS 9 (5+4) High Volume

Bulky local disease + Bone mets

Recommendations : ADT + Docetaxel

( High Volume) ADT initiated

MDACC second opinion :

Octagenarian though fit and Asymptomatic

PSA dropped to 2 within a month

A need to acquire Knowledge to make most of information

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What would be your treatment plan

1. ADT + Monthly denosumab

2. ADT and PSA monitoring

3. ADT and imaging and PSA monitoring

4. ADT + docetaxel

5 .ADT + Abiraterone Acetate

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Foundation Sequencing Results

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Tracking Paul’s PSA

Jan 17

Primary Resistance to ADT within 6 ms

Though PSA had

dropped <1

08 /16 CTC : 0 , MRI of spine no epidural disease,

01/17 Rise in PSA to 2, CTC 1 Bone Scan Stable, MRI stable

PS 0 no new symptoms , urinary frequency better

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What would you advise ?

1. Add Chemo with docetaxel

2 Add Abiraterone

3. Stay the course given lack of imaging progression

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Paul’s life on Chemotherapy Feb 17

He received 5 cycles of chemotherapy reduced dose after 2nd

Neuropathy G2 , Fatigue G2 , Alopecia G2

Initial PSA drop but rise after C3

After C4 urinary frequency ensues

Decision to givea month break

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A month after chemo break (July 2017)

PSA 10 CTC 62

Neuropathy Fatigue Improved, Chemo related Anemia ongoingMRI/ CT assessment : Bone Disease remains controlled

Local Disease exhibiting progression in line with symptoms

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What is your recommendation

1. Continue Chemo but change to cabazitaxel plus carboplatin given mutational load

2 Seek local palliative treatment TURP+/- EBRT

3. Stop Chemo Initiate Abiraterone Acetate

4. Other ?

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Two months of AbirateronePaul Came to my clinic Sep 25 2017

Abiraterone Acetate

PS 0Symptoms ImprovedPSA: <1 CTC: to favorable from 62 to 2

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Make the most of data – adapt to your practice

Monitor patients diligently – details matter

Listen to the need of the patient

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MRC CTU at UCLPatients and their families

Philantropists and Funding AgenciesMr/Ms Stanford AlexanderMr R. Eckstein

Prostate Cancer FoundationMD Anderson Prostate Cancer SPOREDavid H. Koch Center Genitourinary Center FacultyUrology Brian Chapin John Davis John PapadopoulosLouis PistersCurtis PettawayJohn AraujoAna AparicioHirak BasuPaul CornChristopher J LogothetisSumit SubudhiMark TitusShi-ming TuJennifer WangAmado ZuritaBiostatisticsSijin Wen Xuemei Wang

Pathology Patricia TroncosoVictor OrtegaRadiology Tharak BathalaVikas KundraInvernentional RadiologyRahul ShethCancer Systems ImagingPratip BhattacharyaDaniel FrigoDavid Piwnika Worms Imaging PhysicsJames BanksonGenomic MedicineAndy FutrealLily Zhang

Clinical and Tissue Research LeadersIna ProkhorovaMichael ClemingsDoyle BosqueCherie PerezAlexander & Eckstein Laboratory TeamsLaisa Abraham Carol BlandonAnh Hoang Sherie Hodges

IT Development – PrometheusSergio GarzaCindy CarterLisa Pruitt

Research Team Myrto Boukovala MDNikolaos Spetsieris MDJustin Weldon

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Documents

Optimizing prostate cancer therapy strategies 5th ESO-ESMO … · Disclosures –Eleni Efstathiou Research Support/P.I. Janssen, Sanofi-Genzyme, Astellas/Medivation, Innocrin, Tracon