Prostate Cancer

Updates

Russell Szmulewitz, MD

Program Leader, Genitourinary Oncology

Disclosures

▪Advisory board for Pfizer, Bayer, Amgen, Abbvie, Merck, Astellas, Jenssen

▪I will talk about off label or non-FDA approved drugs

▪Have a patent application awarded on GR antagonism in prostate cancer

Outline

▪ Disease states review

▪ Castration-sensitive PC: more

options, better options?

▪ Castration-resistant PC: the old and

the new

3

4

4

Szmulewitz, 2017

Clinical States of PC

Clinically

Localized

Disease

Clinical

Metastases:

Noncastrate mCRPC:

2nd Line

mCRPC:

4th Line

mCRPC:

3rd Line

Non-

Castrate

Rising

PSA Non-

metastatic

CRPC

(nmCRPC)

Castration-

Resistant

Metastatic

(mCRPC):

1st Line

Castration-resistant

Noncastrate

Modified from Scher, ASCO

2015

Death from Prostate

Cancer

CHAARTED E3805 ADT+/-Docetaxel(Updated JCO, 2018)

5Szmulewitz, 2017

→Chemotherapy a consideration for high

volme=4+ bone or visceral

Abiraterone in CSPC

Szmulewitz APAO 20116

▪Latitude (Fizazi et al, NEJM, 2017)▪High risk=metastatic, 2/3 of-GS 8-10, 3 or more bone lesions, measurable visceral disease)

▪OS HR 0.62, median NR vs. 34.7 mo

▪STAMPEDE (James, NEJM, 2017▪Mixed cohort newly diagnosed, 40% non-metastatic

▪OS HR 0.63, 3Yr 83% vs. 76%

Clinically Localized

Disease

Clinical Metastases:

Noncastrate

mCRPC:

2nd Line

mCRPC:

4th Line

mCRPC:

3rd Line

Non- Castrate

Rising

PSA Non- metastatic

CRPC

(nmCRPC)

Castration-

Resistant

Metastatic

(mCRPC): 1st Line

Szmulewitz, 2017

AR antagonists: CSPC

7

▪ENZAMET (Davis et al, NEJM, 2019)▪mCSPC open label Enz+ADT vs. bic +ADT

▪~50% “high volume”, ~15% previous doce

▪HR for death 0.67, PSA-PFS 0.39

▪ARCHES (Armstrong, Szmulewitz et al, JCO 2019 )▪mCSPC double blind ADT+enz/placebo

▪~60% high volume, 18% prior docetaxel

▪ rPFS HR 0.39, PSA-PFS 0.19

▪TITAN (Chi, NEJM, 2019)▪mCSPC ADT+Apa/placebo

▪62.7% high volume, 10.7% prior docetaxel

▪HR OS=0.67, rPFS HR 0.48, 2Yr OS 82 vs. 73%

mCSPC: ADT +…You make the call

8

Abiraterone Enzalutamide Apalutamide

Study (P3) Latitude Stampede Enzamet ARCHES TITAN

Pt. Charac-

terists

High

risk met

50% met,

~50%

localized

mPC,

50% high

volume

mPC,

60% high

vol

mPC, 63% high

volume

Key

Outcomes

OS HR

0.62

3Y FFS HR

0.29

OS HR

0.67

rPFS HR

0.39

OS HR 0.67, rPFS

0.48

Side effects

(%Gr3)

HTN/cardiac (~10%),

LFTs (~10%), edema,

hypoK

Fatigue (1-6%), HTN

(8%), Fall (1%),

Seizure (<1%)

Fatigue (1.5%),

HTN (8.4%), Rash

(6.3%)

Cost/mo ($) ~8K* ~10k ~12k

*Monthly cost less if dose 250mg with food

STAMPEDE Arm H: Radiation to the primary for metastatic CSPC

9Parker et al, Lancet, 2018

▪Unselected population: FFS HR 0.75, P<0001 but no change in OS

▪Pre-specified low-high subgroups:

2020: Metastatic CSPC take homes

10

▪Intensification (ADT+) is standard of care

▪Chemotherapy+ADT superior to ADT for high volume

▪AR Signaling inhibition (ARSI)+ADT superior to ADT

▪Chemo+ARSI UNKNOWN but enzalutamide maybe based on ARCHES

▪RT to primary for low volume M1

▪Chemotherapy+daroloutamide → pending

Szmulewitz, 2017

11

1

1Szmulewitz, 2017

Clinical States of PC

Clinically

Localized

Disease

Clinical

Metastases:

Noncastrate mCRPC:

2nd Line

mCRPC:

4th Line

mCRPC:

3rd Line

Non-

Castrate

Rising

PSA Non-

metastatic

CRPC

(nmCRPC)

Castration-

Resistant

Metastatic

(mCRPC):

1st Line

Castration-resistant

Noncastrate

Modified from Scher, ASCO

2015

Death from Prostate

Cancer

Prior to 2019, sequencing in mCRPCunknown

12Schrader et al, Eur Urol, 2014

Sensitive to both Resistant in sequence

Enza sensitive post abi

Resistant to both!

Szmulewitz, 2017

More Is NOT better (Alliance A031201)

13

14

2nd ARSI not better than chemotherapy

Precision medicine: PC

15Robinson et al, Cell, 2015Szmulewitz, 2017

Precision Medcine: DNA damage repair

~20%-30 of mCRPC harbor mutations in genes

encoding proteins involved in DNA repair such as

BRCA1/2 or ATM (Robinson et al, Cell, 2015; Mateo et

al, NEJM, 2015)

PARP1 inhibitors can induce “synthetic lethality”

ESMO 2019: PROFOUND (Hussain et al) phase

III olaparib vs. ARSI (abi or enz)

Szmulewitz, 2017

Olaparib 300 mg bid

n=94

Physician’s choice‡

n=48

Upon BICR progression,

physician's choice patients were

allowed to cross over to olaparib

Olaparib 300 mg bid

n=162

Physician’s choice‡

n=83

Primary Endpoint

Radiographic progression-free

survival (rPFS) in Cohort A

(RECIST 1.1 & PCWG3 by BICR)

Key Secondary Endpoints

• rPFS in Cohorts A+B

• Confirmed radiographic objective

response rate (ORR) in Cohort A

• Time to pain progression (TTPP)

in Cohort A

• Overall survival (OS) in Cohort AStratification factors• Previous taxane

• Measurable disease

Cohort A:

BRCA1, BRCA2 or ATM

N=245

Cohort B:

Other alterations

N=142

2:1 randomization

Open-label

Key eligibility criteria

• mCRPC with

disease progression

on prior NHA, eg

abiraterone or

enzalutamide

• Alterations in ≥1 of

any qualifying gene

with a direct or

indirect role in HRR*

*An investigational Clinical Trial Assay, based on the FoundationOne® CDx next-generation sequencing testDeveloped in partnership with Foundation Medicine Inc, and used to prospectively select patients harboring alterations in BRCA1, BRCA2, ATM,

BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D and/ or RAD54L in their tumor tissue

‡Physician’s choice of either enzalutamide (160 mg qd) or abiraterone (1000 mg qd + prednisone [5 mg bid])

BICR, blinded independent central review

PROFOUND:

PHASE III STUDY OF OLAPARIB VERSUS ENZALUTAMIDE OR ABIRATERONE

FOR METASTATIC CASTRATION-RESISTANT PROSTATE CANCER WITH

HOMOLOGOUS RECOMBINATION REPAIR GENE ALTERATIONS

◆ Maha Hussain,1 Joaquin Mateo,2 Karim Fizazi,3 Fred Saad,4 Neal Shore,5 Shahneen Sandhu,6

Kim N Chi,7 Oliver Sartor,8 Neeraj Agarwal,9 David Olmos,10 Antoine Thiery-Vuillemin,11

Przemyslaw Twardowski,12 Niven Mehra,13 Carsten Goessl,14 Jinyu Kang,14 Joseph Burgents,15

Wenting Wu,14 Alexander Kohlmann,16 Carrie A Adelman,17 Johann de Bono18

EFFICACY SUMMARY BY COHORT

Cohort A Cohort B Cohorts A+B

N (Olaparib/ Physician’s choice) 162/ 83 94/ 48 256/ 131

rPFS (BICR)

Hazard ratio (95% CI) 0.34 (0.25, 0.47)

P<0.0001

0.88 (0.58, 1.36) 0.49 (0.38, 0.63)

P<0.0001

rPFS (investigator-assessed)*Hazard ratio (95% CI) 0.24 (0.17, 0.34) 0.60 (0.39, 0.93) 0.36 (0.27, 0.47)

ORR (BICR)

%, Olaparib vs Physician’s Choice

Odds ratio (95% CI)

33.3 vs 2.3%

20.86 (4.18, 379.18)

P<0.0001

3.7 vs 8.3%

Not calculated†

21.7 vs 4.5%

5.93 (2.01, 25.40)

OS (interim)

Hazard ratio (95% CI) 0.64 (0.43, 0.97)

P=0.0173

0.73 (0.45, 1.23) 0.67 (0.49, 0.93)

Denotes multiplicity-controlled endpoint

* Pre-specified sensitivity analysis†N=2 responders each for olaparib vs physician’s choice.

PARPi by molecular abnormality

Wabida, ESMO, 2018; CCR, 2020 19

BRCA2

CDK12

ATM

BRCA1

CHEK2

PPP2R2A

RAD51B

RAD54L

Olaparib Physician's choice

n=8147

6128

6224

85

75

64

41

32

NR

Fre

quen

cy

10.84 (9.17, 13.08)3.48 (1.74, 3.65)

5.09 (3.61, 5.52)2.20 (1.71, 4.83)

2.07 (1.38, 5.52)1.84 (1.71, 3.71)

5.59 (1.64, 11.99)3.35 (1.38, NR)

2.69 (1.77, 3.91)

10.89 (1.61, 14.75)1.77

7.20 (3.71, 7.39)2.41 (1.81, 3.02)

5.36 (3.61, 6.21)4.70 (1.84, 7.26)

0 2 4 6 8 10

Hussain, ESMO, 2020

Rucaparib, TRITON2

Molecularly Targeted: PSMA

▪ PSMA is a membranous protein overexpressed in

prostate cancer

▪177Lu-PSMA-617 is radiopharmaceutical utilized

outside of the US with pending phase III trials

▪ Single center (N=90) single-arm study.

20Yadav MP, Ballal S, Bal C, et al. Clin Nucl Med. 2020;

77Lu-PSMA-617 is active. Magnitude and

duration of benefit in comparison to other

standards of care pending PIII VISION trial

Molecular biomarkers for PD1/PDL1?

Manogue, Oncologist, 2019 21

KEYNOTE-991: Unselected, Phase III ADT+ENZ+pembro/placebo

Other Molecular Targets-ARSI combo

▪AKT/PI3K (enriching for PTEN deletion)▪E.g.: Ipatasertib/placebo Plus Abiraterone-Pred (IPATential150)

▪GR antagonist▪PCCC Enz+/-Mifepristone study negative

▪Ongoing Enz+relacorilant with significant biomarker collection for future enrichment

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Conclusions

▪ Multiple options in mCSPC, but ADT+ is clear standard of care

▪ Sequencing/Addition of multiple ARSI unlikely to be beneficial

▪ PARPi is an emerging, bona fide standard for 2nd/3rd line mCRPC

▪77Lu-PSMA-617 will hopefully read out positive this year

▪ Molecularly targeted therapies to other targets pending

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