Parpi in Prostate Cancer

Pongwut Danchaivijitr, MD
July 31st, 2021

TH-7635 Exp 29/08/2021

 Slide Credits

TH-7635 Exp 29/08/2021

Overview
§ DNA Repair and Prostate Cancer
§ Germline VS Somatic DDR Testing
§ Parpi in Prostate Cancer
§ Parpi without DDR alteration

TH-7635 Exp 29/08/2021

How Does DNA Repair Work in Normal Cells?

TH-7635 Exp 29/08/2021

 DNA is Constantly Damaged and Repaired

Perfect

Repair
Reduced efficacy
DNA Imperfect of DNA damage
STOP Mutation
response promotes
carcinogenesis
UV light 1000s of
Ionizing radiation events/day:
Carcinogens Failed
Replication errors
ssDNA and STOP
dsDNA breaks
Replication collapse
and cell death
Griffiths. An Introduction to Genetic Analysis. 7th ed. 2000. TH-7635 Exp 29/08/2021
 DNA Damage Repair (DDR) Pathways
§ DDR has evolved to maintain DNA sequence fidelity
§ Several repair pathways exist, depending on type of DNA damage
‒ Single-strand DNA breaks
‒ PARP, poly(ADP-ribose) polymerase
‒ MMR
‒ Double-strand DNA breaks
‒ BRCA1/2, breast cancer genes

O’Connor. Mol Cell. 2015;60:547.

TH-7635 Exp 29/08/2021
 Single-Stranded DNA Damage

Repair Pathways Repair Action Genes/Proteins Involved

Fixes small
insertions/deletions
Mismatch repair (MMR)* MSH2, MSH6, MLH1, PMS2
occurring during normal
DNA replication
Removes bulky DNA lesions
Nucleoside excision repair XPA-G, ERCC1-8, CSA/B,
such as those caused by
(NER) RPA, RAD23A/B, ATR
UV light
Rejoins broken strands
Single-stranded break repair PARP1, POLB, XRCC1, ATR,
during base excision repair
(SSBR) MUTYH
(BER)
*Microsatellite instability (MSI) is a measure of mismatch repair deficiency. Pembrolizumab has tumor-agnostic FDA approval for MSI-H tumors.

Mateo. Euro Urol. 2017;71:417. TH-7635 Exp 29/08/2021

 Double-Stranded DNA Damage

Repair Pathways Repair Action Genes/Proteins Involved

Homologous
Flawless repair of dsDNA breaks BRCA2, BRCA1, PALB2, ATM
recombination (HRR)

Nonhomologous end
Repairs DNA but creates deletions ATM, DNA-PK
joining (NEJ)

Mateo. Euro Urol. 2017;71:417. Aparicio. DNA Repair (Amst). 2014;19:169. TH-7635 Exp 29/08/2021
 Role of PARP in Repair of SSB in Normal Cells

§POLβ PARP
Lig3 PNK PARP
PARP PARP
XRCC1

Single-stranded PARP1 binds PARP1 attracts PARP1 Repair

DNA damage to DNA cofactors to modifies itself complete
fix damage to detach

Stuck on You
§ PARP1 must modify itself to detach
§ PARP inhibitors prevent this modification

Ohmoto. Onco Targets Ther. 2017;10:5195. Murai. Cancer Res. 2012;72:5588.

Murai. Mol Cancer Ther. 2014;13:433. Pommier. Sci Transl Med. 2016;8:362ps17. TH-7635 Exp 29/08/2021
 2 Pathways to Repair Double-Stranded DNA Damage

Homologous Recombination Nonhomologous End Joining

BRCA1 blocks 53BP1, 53BP1 keeps MRE11 away
MRE11 complex resects ends from free ends
BRCA1 53BP1
53BP1
MRE11

BRCA2 recruits RAD51, PALB2 Ends chewed back,

glued together
BRCA2 PALB2 BRCA1
Sister chromatid
Repair introduces deletions
Repair matches original
Aparicio. DNA Repair (Amst). 2014;19:169. TH-7635 Exp 29/08/2021
 Synthetic Lethality With PARP Inhibition is Produced by
Conditional Drug Sensitivity in HRR-Deficient Cells
HR Repair of ssDNA Break
dsDNA Breaks? Repair? Cell Viability?

Normal Cells Yes

Normal Cells + PARPi Yes

HRR-Deficient Cells Yes

HRR-Deficient Cells + PARPi

Ashworth. JCO. 2008;26:3785. Lord. Nat Rev Cancer. 2016;16:110. Lord. Science. 2017;355;1152. TH-7635 Exp 29/08/2021
DNA Repair Defects in Prostate Cancer

TH-7635 Exp 29/08/2021

 Genomic Alterations in Prostate Cancer Progression
Normal Curable Compromised DNA repair
prostatic
epithelium
Loss of 8p Loss of PTEN, 13q (RB1), 5q (CHD1),
Prostatic (NKX3.1)? 16q, 6q, 3p (FOXP1, SHQ1)
Epigenomic changes, intraepithelial Gain of 8q, 3q (PIK3CA)
including GSTP1 neoplasia
hypermethylation
Localized
cMYC PCa Inactivation of p53, RB1, CDK12
PCA3
AMACR Activation of
β-catenin, wnt Metastatic Anaplastic/
PCa NE PCa
ETS gene family Loss of APC
activation via fusion EZH2 Tx
with TMPRSS2 or other AR gene expression
AR-driven genes Mutation/gain/V7 Castration-
resistant
Incurable PCa
Mutations in SPOP, FOXA1, epigenetic regulators
References in slidenotes. TH-7635 Exp 29/08/2021
 Genomics of Advanced Prostate Cancer
§ Multi-institutional clinical Genetic Alterations Enriched in mCRPC vs
sequencing analysis of bone or Treatment-Naive Primary PCa
soft tissue tumor biopsies from 20 TP53
150 patients with mCRPC SPOP
PTEN
FOXA1
‒ 90% of patients harbored a 10
mCRPC
alterations
CTNNB1
clinically actionable, somatic or FANCG
APC AR Max

germline molecular alteration All values BRCA2

–log10(p) MLL2
0 GNAS Min
‒ Multiple pathways represented: 5 0 5 10 15 20 25
WNT, PI3K, AR, DNA repair, cell Primary mCRPC Enriched
Enriched
cycle

Robinson D et al. Cell. 2015;161:1215-1228. TH-7635 Exp 29/08/2021

 DNA Repair Defects in mCRPC
§ 32/150 (21.3%) mCRPC patients with biallelic DNA repair mutations
Patient
Cases With
DNA Repair
Defects

Mutations
Identified
in BRCA2,
ATM

Reprinted from Robinson D, et al. Integrative clinical genomics of advanced prostate cancer. Cell.
2015;161(5):1215-1228. Copyright © 2015 with permission from Elsevier Inc. TH-7635 Exp 29/08/2021
 DNA Repair Defects in mCRPC: Enrichment Analysis in
Primary vs Metastatic Tumors
Tumor Samples (N = 918) Genomic Alteration Frequency
50
Significance Amplification/mutation
Primary 30 (Fisher’s qvalue) Homdel/mutation

Altered Primary Samples (%)

Mutation PTEN
SPOP
TP53

583 10
Primary Metastases
DNA repair defects: 11% DNA repair defects: 21%

KMT2C

335 5
RYBP/FOXP1
MYC
KMT2D

ZFHX3 FOXA1

RB1

CTNNB1 BRCA2
SPEN CDK12 APC

Metastasis GRIN2A CCND1

IDH1 ANKRD11 MED12 JAK1
RNF43 USP28 FAT1 AR
USP7 ASXL1 IGF2R
CARD11 CHD8
SAMD9
0 ERF
GNAS
PREX2
MGA

0 5 10 30 50
Altered Metastatic Samples (%)
Armenia J, et al. ASCO 2017. Abstract 131. TH-7635 Exp 29/08/2021
 1 in 10 Men With Metastatic Prostate Cancer Have
Germline DNA Repair Mutations
Distribution of Presumed Pathogenic § 11.8% (82/692) of men with metastatic
Germline Mutations advanced prostate cancer inherited a
RAD51C, 1%
MSH6, 1%
germline DNA repair mutation vs 4.6% of
MRE11A, 1%
MSH2, 1% BRIP1, 1%
499 men with localized disease
GEN1, 2% FAM175A, 1%
PMS2, 2%
NBN, 2%
Presumed Pathogenic Germline Mutations
ATR, 2% in Metastatic Cases (N = 692)
RAD51D, 4%
Gene No. of Mutations % of Men
PALB2, 4%
BRCA2 37 5.35
BRCA2, 44%
BRCA1, 7% ATM 11 1.59
CHEK2, 12% CHEK2* 10 1.87
BRCA1 6 0.87
ATM, 13% *n = 534; data censored for metastatic cases with inadequate
sequencing.

Pritchard CC, et al. N Engl J Med. 2016;375:443-453. TH-7635 Exp 29/08/2021

 More Aggressive Disease in BRCA1/2 and ATM Mutation
Carriers
Entire Cohort Localized Only
1.0 All subjects (N = 799) 1.0 Initial diagnosed with localized diseases
(n = 674)
0.8 0.8
PCa-Specific Survival

PCa-Specific Survival
0.6 0.6 Nonmutation carrier
Mutation carrier
0.4 0.4 Nonmutation carrier (censored)
Mutation carrier (censored)
0.2 0.2

0 Log-rank P = 3.7 x 10-10 0 Log-rank P = .0013

0 5 10 15 20 25 30 0 5 10 15 20 25
Yrs to Death Yrs to Death
Median Survival, Yrs 95% CI Median Survival, Yrs 95% CI
Mutation carrier 5.0 2.1-7.9 Mutation carrier 11.0 NA
Nonmutation carrier 16.0 15.2-16.8 Nonmutation carrier 18.0 17.2-18.8
Na R, et al. Eur Urol. 2017;71:740-747. TH-7635 Exp 29/08/2021
 Therapeutic Implications of
DNA Repair Defects in Advanced Prostate Cancer

TH-7635 Exp 29/08/2021

 DDR Deficiencies and Therapeutic Index
§ Mutations in individual DNA repair genes can result in inactivation of
one of the DNA repair pathways
‒ For example, BRCA2 loss results in cells deficient in HR DNA repair
§ Such cancer cells become dependent on the remaining intact DNA
repair pathways
§ Targeting these remaining intact pathways with inhibitors can result in
a profound tumor-specific DNA repair deficiency
‒ For example, targeting PARP, a key enzyme in BER DNA repair, in cancer
cells with an HR DNA repair deficiency results in tumor-specific cell killing

Lord CJ, et al. Science. 2017;355:1152-1158. TH-7635 Exp 29/08/2021

 PARP Biology
§ PARP (polyADPribose polymerase) enzymes play a key role in the repair of
ssDNA breaks via BER pathway
§ Bind directly to sites of DNA damage
§ Once activated, uses NAD as a substrate to add large, branched chains of
poly(ADP-ribose) polymers (ie, PARylation) to itself and interaction partners
§ Recruits other DNA repair enzymes to site of damage

DNA damage
PARP
NAD+ Nicotinamide XRCC1 Lig3
+ pADPr PNK
Polß

Ohmoto A, et al. Onco Targets Ther. 2017;10:5195-5208. TH-7635 Exp 29/08/2021

 PARPi Leads to Increase in dsDNA Breaks
§ Inhibition of PARP ssDNA
breaks
‒ Prevents recruitment of PARP inhibition
DNA repair enzymes to PNK 1
ssDNA breaks or traps DNA
Polβ
XRCC1
PARP on DNA DNA
PARP Lig III
‒ Leads to failure of ssDNA
repair and accumulation
of ssDNA breaks
During S-phase, replication fork is
‒ Replication fork is arrested arrested at site of ssDNA breaks
at damage, produces dsDNA Degeneration into
breaks dsDNA breaks

Ohmoto A, et al. Onco Targets Ther. 2017;10:5195-5208. TH-7635 Exp 29/08/2021

 Synthetic Lethality Hypothesis

PARP function PARP function PARP function

BRCA function BRCA function BRCA function

Normal cell Normal cell Cancer cell

Non-BRCA mutation carrier BRCA mutation carrier BRCA mutation carrier
(1 allele lost) (both alleles lost)

DNA damage DNA damage DNA damage

PARP inhibitor PARP inhibitor PARP inhibitor

PARP function PARP function PARP function

BRCA function BRCA function BRCA function
Repair, Repair, Repair, Repair, Repair, Cell Death
survival survival survival survival survival
Bryant HE, et al. Nature. 2005;434:913-917. Farmer H, et al. Nature. 2005;434:917-921. TH-7635 Exp 29/08/2021
 PARPi in BRCA1/2 Mutation Carriers
§ Phase I study of olaparib in pts with
solid tumors, including prostate
cancer (N = 60)
‒ 19 of 23 BRCA1/2 mutation carriers
evaluable
‒ 3 prostate cancer pts, 1 with CRPC
and BRCA2 mutation
§ Objective antitumor activity seen
only in mutation carriers, except 1
pt with history suggestive of BRCA
deficiency
Fong PC, et al. N Engl J Med. 2009;361:123-134.
§ Partial radiologic tumor response
with 4-mos of olaparib observed in
8 pts with advanced ovarian
cancer
‒ 66% peritoneal tumor nodule
reduction in pt with a strong
family history suggestive of BRCA
deficiency
‒ Complete regression of peritoneal
tumor in pt with BRCA1 mutation
TH-7635 Exp 29/08/2021
Mismatch Repair Defects

TH-7635 Exp 29/08/2021

 MMR Mutations in mCRPC

Patient Cases With DNA Repair Defects

§ 3/150 (2%) had MMR mutations

§ 4/150 (2.7%) were MSI-high

Reprinted from Robinson D, et al. Integrative clinical genomics of advanced prostate cancer. Cell.
2015;161(5):1215-1228. Copyright © 2015 with permission from Elsevier Inc. TH-7635 Exp 29/08/2021
 MMR Deficiency Across 12,019 Solid Tumors
18

With MMR Deficiency (%)

16

Proportion of Tumors
14
12 Late stage
10 Early stage
8
Prostate
6
4
2
0
l a s r s a a a a a y a a
t
a a
ria om cie om nce mor oma om om com om om om cie oma cer cer mar mas cer
s
o m a tom ors
e n n n n n n i n m s m
o m rci gna rcin l Ca e Tu rcin rcin rci Sar arci Sarc ela nan rcin Ca Can Pr cino Can arci ino bla Tu
d ca li ca c a n a ca c a e C l M li g a n g n r g C rc io e
En eno Ma no ervi ocri ar C no gio erin oid nea eal Ma noc aria Lun now l Ca Lun ast Ca Gl issu
d a l d e C nd llu Ad l e n
a Ut hyr rito Uv act Ade l Ov ell k li a ll e n T
ic A stin al A e ce ic hol T e r ic lia l-C Un the l-Ce Br ctio oft
r o P T i S
st te ect ur ato tat C r l t e l Ep ma
l un
Ga ll In lor Ne ep ros lo n ita crea ith Sma e S icJ
a p c - r
a Co rH P ne Ge Pan one rfa Non as
t
Sm e it o le N Su o g
Liv r a
ag
ope F e m
r ian p h
tr r a o
Re the Ov Es
O nd
ala
e
hag
op
Es

Dung LT, et al. Science. 2017;357:409-413. TH-7635 Exp 29/08/2021

 MMR Defects are Associated With High Gleason Grade
MSH2 IHC § 1.2% (14/1176) of primary adenocarcinomas
and NEPC had MSH2 protein loss
§ Pathology and MSH2 loss
‒ Primary Gleason pattern 5 enriched for MSH2
loss: 8% (7/91)
‒ MSH2 loss in patients with any other Gleason
score: < 1% (5/1042); P < .05

Guedes LB, et al. Clin Cancer Res. 2017;23:6863-6874. TH-7635 Exp 29/08/2021
 MMR Defects Generate Many Nonsense Changes in
mCRPC (> 1000)
§ 3/150 (2%) had MMR mutations
MSI Analysis:
Hypermutated vs Nonhypermutated CRPC § 4/150 (2.7%) were MSI-high
0.50
MSI Positive
‒ 13 mut/Mb (Pt #149): MSH2
148 150
‒ 21 mut/Mb (Pt #147): no MMR
Fraction Unstable Loci

0.40
149
0.30
mutation
147
0.20 ‒ 23 mut/Mb (Pt #148): MSH2
32, 41, 49, 67, 93
0.10 ‒ 25 mut/Mb (Pt #150): MSH2 and
0
MSI Negative MLH1
0 500 1000 1500
Nonsynonymous Mutations § Neoantigens: novel targets for
immunotherapy?
Robinson D, et al. Cell. 2015;161:1215-1228.
TH-7635 Exp 29/08/2021
Conclusions
§ DNA repair mutations are common in prostate cancer, particularly mCRPC
‒ Both somatic and germline mutations can lead to DNA repair defects
‒ Importance of biallelic mutation/inactivation
‒ Implications for genetic testing and therapy
§ HR DNA repair mutations sensitize to PARP inhibitors
‒ “Synthetic lethality” hypothesis in action
‒ Limitations?
§ MMR mutations are rare...but may sensitize to immune checkpoint
inhibitors
TH-7635 Exp 29/08/2021
Which Patients With Prostate Cancer Should
Undergo Somatic Mutation Testing?

TH-7635 Exp 29/08/2021

 Evaluation for Precision Cancer Treatment in mCRPC:
Somatic Genetic Testing
§ Current assays are typically intended for somatic or germline
mutations, but not both
‒ Important to understand your test, what it covers, and its limitations (eg,
tumor vs cell-free DNA vs germline)
§ Some commercial tumor tests will report selected “secondary/
incidental” germline mutations
§ Important to discuss and consent to this possibility prior to testing
individual patients

Ngeow J, et al. NPJ Genom Med. 2016;1:15006.

TH-7635 Exp 29/08/2021
 Actionable Mutations in CRPC
99 AR: AR amplified or mutated
100 PIK3: PTEN mutated/lost, AKT activated, PIK3CA amplified
DNA REPAIR: ATM, BRCA1, BRCA2, RAD51, FANCA altered
BRAF/RAF: Gene fusion
80
CDK inhibition: CCND1 amplification, CDKN2A/B loss
Percentage

63 65 WNT: WNT pathway events upstream of APC/CTNNB1

60 Germline: BRCA2, BRCA1, ATM in this cohort
47
40
19
20
7 5 8
3
0
ion ut -AR K ir F1 ion T ine
at /M n PI3 epa RA it WN l
b err A mp le No
NAR RAF
/
In hib G erm
A AR ab D B K
tive o n CD
a ti
o r m Ac
Inf
TH-7635 Exp 29/08/2021
Robinson D, et al. Cell. 2015;161:1215-1228.
Summary: Consideration of Germline and/or Somatic
Testing by Prostate Cancer Risk Category
§ For very low risk: consider germline testing if strong family history;
somatic testing not recommended
§ For low/intermediate/favorable risk: consider germline testing if
strong family history, tumor testing if it would impact management
§ For high/unfavorable risk disease: strongly consider germline testing,
recommend if strong family history; somatic testing not recommended
§ Regional/metastatic disease: strongly consider germline testing,
recommend if strong family history; consider tumor testing for HRD,
MSI, or MMR

TH-7635 Exp 29/08/2021

Testing for Tumor (Somatic) DNA Mutations

TH-7635 Exp 29/08/2021

 Somatic Mutations in CRPC: Implications for Targeted
Therapy
§ Patients with metastatic CRPC
‒ Actionable molecular alterations: 90%
‒ DNA repair pathway alterations: 23%
‒ Confirmed germline findings: 8% to 10%

Robinson. Cell. 2015;161:1215. Shevrin. Asian J Androl. 2020;18:586. Mateo. Eur Urol. 2017;71:417. TH-7635 Exp 29/08/2021
What Tests Are Available to Test for Tumor DNA
Mutations?
§ Tissue or “liquid” biopsy (eg, CTC, ctDNA) for multiple genes
‒ Examples of sample types and commercial tests available
‒ Tissue: Foundation One, Tempus
‒ “Liquid” blood-based: EPIC, RareCyte (CTC); Guardant360, Foundation
(ctDNA)
§ Different tissue sources: bone, lymph node, liver, soft tissue
‒ Yield in obtaining cancer tissue ranges from 30% to 75%
§ No standardized reporting of somatic mutations at present

TH-7635 Exp 29/08/2021

 What Tumor (Somatic) Genetic Testing Might Show
§ DDR mutations including BRCA and MSI
‒ Could be either germline or somatic or both
‒ Dedicated germline testing should be done to determine whether the DDR
mutation is of germline origin[1]
‒ Positive germline testing has the same implications as discussed previously for
genetic counseling and “cascade” testing of family members
§ Other pathogenic mutations as potential targets, eg, PI3K
§ Results of somatic DNA testing are likely to change over time due to the
genetic instability of tumor DNA[2]
‒ Archival tissue will likely be different from metastatic tissue
‒ Serial tumor or liquid biopsies may help identify new actionable mutations
1. Cheng. Clin Genitourin Cancer. 2017;15:625. 2. Friedlander. Am Soc Clin Oncol Edu Book. 2018;37:358.
TH-7635 Exp 29/08/2021
Summary
§ BRCA2 germline deficiency is the most common reason for HRR deficiency in
prostate cancer
§ Inhibition of single-strand damage repair by PARP1 in men with BRCA2
deficiency results in “synthetic lethality”
§ Identification of men with DDR deficiencies by germline and/or somatic
testing leads to a specific therapeutic paradigm
‒ HRR deficiency especially BRCA2: PARP inhibitors or platinum-based
chemotherapy
‒ MMR with MSI-H: pembrolizumab
§ Genetic counseling is indicated for men with pathogenic germline mutations
TH-7635 Exp 29/08/2021
Clinical Development: PARP Inhibitors for BRCA1/2-
Mutant or Homologous Recombination–Deficient
Prostate Cancer

TH-7635 Exp 29/08/2021

 PARPi Sensitivity Correlates With Platinum Sensitivity
§ Platinum cross-resistance with Tumor Response to Olaparib in Ovarian
BRCA1/2 Subpopulation
PARPi apparent from first-in- 24 Platinum Platinum Platinum
human olaparib trial refractory resistant sensitive

Platinum-Free Interval (Mos)

§ Cross-resistance not absolute; one 18 CR or PR Rs = 0.33
P = .03
(RECIST criteria and/or GCIC)
can work after the other Stable disease for > 4 mos (RECIST)
12 Progressive disease (RECIST)
‒ Olaparib active in platinum-
resistant ovarian cancer, but very 6
little activity in platinum-refractory
disease 0
During After 0-6 mos After > 6 mos
‒ Platinum can work in PARPi- treatment
refractory disease Time of Relapse During/After
Platinum-Based Chemotherapy

Fong PC, et al. J Clin Oncol. 2010;28:2512-2519. TH-7635 Exp 29/08/2021

 PARP Inhibitor Antitumor Activity
§ Dual cytotoxic mechanisms of PARP enzyme PARPi IC50, Relative PARP
inhibition by PARPi nm Trapping
Potency
‒ Base excision repair blockade via catalytic
inhibition Talazoparib 4 ~ 100
Olaparib 6 1
‒ PARP trapping on DNA, which induces
double-strand breaks Rucaparib 21 1
Niraparib 60 ~2
§ Potency of PARP trapping: talazoparib >>
Veliparib 30 < .02
niraparib = olaparib = rucaparib >> veliparib
‒ Talazoparib is a potent PARP trapper;
veliparib may not trap PARP
‒ Iniparib does not inhibit PARP

Pommier Y, et al. Sci Transl Med. 2016;8:362ps17. Lim JSJ, et al. Cancers (Basel). 2017;9:E109. TH-7635 Exp 29/08/2021
TOPARP-A: PARPi in HR-defective
Advanced Prostate Cancer

TH-7635 Exp 29/08/2021

 TOPARP Trial Design: Olaparib in Metastatic Prostate
Cancer
§ Investigator-initiated, open-label, multistage phase II study with adaptive
design focused on predictive biomarker identification
‒ Part A: test set; all comers
‒ Part B: validation set; biomarker preselected patients
‒ Part C: possibility to proceed to randomized phase II study of olaparib vs PBO
Patients with mCRPC, Study Objectives
progression on 1-2
Olaparib* 400 mg BID § Evaluate antitumor activity in mCRPC
lines of taxane-based
chemotx, ECOG PS 0-2, (n = 45) § Identify and clinically qualify suite of
no prior platinum or *Tabs. predictive biomarkers for PARPi efficacy
PARPi in CRPC

Mateo J, et al. N Engl J Med. 2015;373:1697-1708. TH-7635 Exp 29/08/2021

 TOPARP: Endpoints
§ Primary endpoint: response rate § Exploratory endpoints
‒ Response per RECIST 1.1 ‒ Study of diffusion-weighted MRI as
response biomarker
‒ PSA decline ≥ 50% (PCWG-2)
‒ QoL studies (pain improvement)
‒ CTC conversion (≥ 5 to < 5/7.5 mL);
confirmed by second assessment ‒ Circulating cell-free DNA and single
≥ 4 wks later CTCs: potential response and
resistance biomarkers
§ Secondary endpoints
‒ PFS, rPFS, OS, time to PSA progression
(PCWG-2), time to radiologic
progression, rate of CTC conversion,
DoR, safety/tolerability

Mateo J, et al. N Engl J Med. 2015;373:1697-1708. Goodall J, et al. Cancer Discov. 2017;7:1006-1017. TH-7635 Exp 29/08/2021
 TOPARP: Trial Status
PART A Stage 1:
30 molecularly unstratified patients
Ho RR: 5%
≥ 15 respond ≤ 2 respond 3-14 respond Ha RR: 20%
α = .02, β = .10
Recruit a further
15 patients (stage 2)

PART A Stage 2:
Total of 45 molecularly unstratified patients

≤ 5 responders ≥ 23 responders 6-22 responders

End of trial Investigate if potential biomarkers of

PART C: Randomized response can be identified
clinical trial
Potential
biomarker found

TOPARP-A: published PART B:

TOPARP-B: almost completed Biomarker-preselected Ongoing
TOPARP-C: in development patients

Mateo J, et al. N Engl J Med. 2015;373:1697-1708. TH-7635 Exp 29/08/2021

 TOPARP-A: Genomic DNA Repair Aberrations in Patients
With mCRPC
Response to Olaparib
No Response to
Olaparib*
§ 16 of 49 evaluable
Patient no.
Time on tx, wks
17 15 14 20 30 39 35 36 1 6 5 26 48 8 16 11 7 12 44 31 50
24 36 36 48 44+ 44+ 40+ 57 73 16 58 19 39 62 40+ 12 12 11 24 8 8
patients responded
to olaparib
DNA Repair Mutations

Biomarker positive† X X X X X X X X X X X X X X X X
BRCA2
ATM
FANCA ‒ 14 of 16 (88%)
CHEK2
BRCA1 biomarker-
PALB2
HDAC2 positive patients
RAD51
MLH3
ERCC3
‒ 2 of 33 (6%)
MRE11
NBN
biomarker-
negative patients
Frameshift mutation Single copy deletion Missense mutation Germline event
Stop gain Homozygous deletion Copy-neutral loss of
heterozygosity
*28 additional biomarker-negative patients without a response to olaparib.
†Biomarker positive: homozygous deletions, deleterious mutations, or both in DNA-repair genes.

Mateo J, et al. N Engl J Med. 2015;373:1697-1708. TH-7635 Exp 29/08/2021

 TOPARP-A: PFS and OS by Presence of DNA Repair
Defects
Radiologic PFS OS
1.00 1.00
Log-rank P < .001 Log-rank P = .05
Proportion of Patients

Biomarker positive,

Proportion of Patients
0.75 Biomarker positive, 0.75
median: 9.8 mos median: 13.8 mos

0.50 0.50

Biomarker negative, Biomarker negative,

0.25 0.25 median: 7.5 mos
median: 2.7 mos

0 0
0 1 2 3 4 5 6 7 8 9 10 1112 13 14 15 16 1718 19 20 0 1 2 3 4 5 6 7 8 9 10 1112 13 14 15 16 1718 19 20
Mos Since Trial Entry Mos Since Trial Entry

Mateo J, et al. N Engl J Med. 2015;373:1697-1708. TH-7635 Exp 29/08/2021

 TOPARP-A: Changes in PSA and CTC Count by Presence of
DNA Repair Defects
PSA CTC Count
300 150
Biomarker negative
Mean Percent Change in PSA

Mean Percent Change in PSA

250
100
200 Biomarker negative Biomarker positive
150 50

100 0
Biomarker positive
50
-50
0
-50 -100

-100 -150
0 12 24 36 48 60 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60
Wks Since Treatment Initiation Wks Since Treatment Initiation

Mateo J, et al. N Engl J Med. 2015;373:1697-1708. TH-7635 Exp 29/08/2021

 TOPARP-A: Safety

AEs in ≥ 10% of Patients, n (%) All Grade Grade ≥ 3 AEs in ≥ 10% of Patients, n (%) All Grade Grade ≥ 3
Anemia 38 (76) 10 (20) Creatinine elevation 7 (14) 0
Fatigue 29 (58) 6 (12) Chest pain 7 (14) 0
Nausea 18 (36) 0 Constipation 7 (14) 0
Arthralgia 15 (30) 1 (2) Cough 7 (14) 0
Anorexia 14 (28) 1 (2) Headache 6 (12) 0
Dyspnea 14 (28) 1 (2) Hyponatremia 6 (12) 1 (2)
Back pain 11 (22) 1 (2) Leukopenia 6 (12) 3 (6)
Vomiting 10 (20) 0 Dizziness 5 (10) 0
Weight loss 9 (18) 0 Neutropenia 5 (10) 2 (4)
Diarrhea 8 (16) 0 Thrombocytopenia 5 (10) 2 (4)
Peripheral edemas 8 (16) 1 (2)
Bone pain 8 (16) 1 (2)
Pain in extremities 8 (16) 0
Mateo J, et al. N Engl J Med. 2015;373:1697-1708. TH-7635 Exp 29/08/2021
TOPARP-B: A Phase II Randomized Trial of the Poly(ADP)-
Ribose Polymerase (PARP) Inhibitor Olaparib for Metastatic
Castration Resistant Prostate Cancers (mCRPC) with DNA
Damage Repair (DDR) Alterations.

§ Joaquin Mateo, Nuria Porta, Ursula Brigid McGovern, Tony Elliott, Robert J Jones, Isabel
Syndikus, Christy Ralph, Suneil Jain, Mohini Anna Varughese, Omi Parikh, Simon J.
Crabb, Susana Miranda, George Seed, Claudia Bertan, Aude Espinasse, Peter Chatfield,
Diletta Bianchini, Emma Hall, Suzanne Carreira, Johann S. De Bono
§ An investigator-initiated trial on behalf of the TOPARP investigators

TH-7635 Exp 29/08/2021

51
Background
§ DNA damage repair (DDR) gene aberrations
found in 20-25% of mCRPC
‒ Germline and/or somatic
‒ BRCA2 is commonest altered DDR gene (10%)

§ PARP inhibitors synthetic lethal with many DDR

gene aberrations including BRCA2, BRCA1,
PALB2, ATM, and CDK12
‒ Different magnitudes of sensitization
‒ Bi-allelic loss usually required to sensitize

§ PARP inhibitors already approved for treating

ovarian and breast cancers
Murai et al, Cancer Res 2012
52
Joaquin Mateo, MD PhD TH-7635 Exp 29/08/2021
 Study Design I
§ Multi-stage, adaptive Phase II trial design, for predictive biomarker qualification based on response rate
‒ Test set : No molecular selection (TOPARP-A)
‒ DDR gene aberrations associated with responses to olaparib (Mateo et al, NEJM 2015)
‒ Validation set: Molecularly selected (TOPARP-B)

§ Study objectives:
• To evaluate the anti-tumor activity of olaparib in mCRPC
• To identify predictive biomarkers of PARPi sensitivity in mCRPC

• Test set (TOPARP-A): Two-stage design based on H0: p0=0.05; Ha: p1=0.20; α=0.02 and β=0.10
• Validation set (TOPARP-B): One-stage A’Hern design, which assumed H0: p0=0.3; Ha: p1=0.5; α=0.05 and β=0.15. Successful
(validation of biomarker) if >19/44 respones (40%).

53
Joaquin Mateo, MD PhD TH-7635 Exp 29/08/2021
Study Design II
• TOPARP-A evaluated olaparib at 400mgs twice daily (BID) tablets.
• But olaparib now approved in breast and ovarian as 300mgs BID tablets
• Several trials indicate that dose matters to antitumor activity (Fong et al, NEJM 2009).

To validate TOPARP-A we therefore

elected to study both the TOPARP-
A dose (400mgs BID, tablets) and
the dose used in the ovarian and
breast registration Phase III trials
(300mgs BID tablets)

54
TH-7635 Exp 29/08/2021
Joaquin Mateo, MD PhD
Eligibility Criteria
Biomarker-driven selection
• Prescreening for DDR alterations: primary tumor or M1 biopsies, either archival or freshly
collected samples underwent amplicon-based targeted NGS at academic central lab (ICR,
London).
• Biomarker definition: “one or more alterations, putatively pathogenic mutations or homozygous
deletions, in genes related to DNA repair or PARPi sensitivity.” (biallelic events not mandated)
• mCRPC after at least 1 but no more than 2 lines of taxane-based chemotherapy
• PSA and/or radiological progression at the time of randomization
• ECOG 0-2
• Hb>9g/dl, ANC>1.5x109/L, Platelets>100x109/L, Bilirubin<1.5x ULN, AST and ALT<2.5x
ULN (<5x ULN if liver mets), Creatinine<1.5x ULN, Albumin >25g/dl.

• Compared to TOPARP-A, requirement of CTC counts≥5 at baseline was removed if patients

had measurable disease>2cm: only 51% were evaluable for CTC conversion.

55
Joaquin Mateo, MD PhD TH-7635 Exp 29/08/2021
 Results: Prescreening for DDR alterations

32.7% 21.4% 21.4% 7.1% 21.4%

BRCA1/2 ATM CDK12 PALB2 OTHER
Recruitment: 1st Apr 2015 to 30th Aug 18;.Snapshot: 19th March 2019;.Median follow-up: 20.5 months
56
TH-7635 Exp 29/08/2021
Joaquin Mateo, MD PhD
 Results: Study Population (baseline)
Dose group Total Dose group
Total (N=98)
300 mg (N=49) 400 mg (N=49) (N=98) 300 mg (N=49) 400 mg (N=49)
Age at trial entry, mean (SD) 67.6 (7.6) 67.7 (7.4) 67.4 (7.8) BRCA1/2 31 14 17
Previous treatment n % n % n % ATM 21 10 11
Docetaxel 98 100 49 100 49 100 CDK12 20 14 6
Cabazitaxel 37 37.8 15 30.6 22 44.9 PALB2 5 1 4
Abiraterone and/or Enzalutamide 88 89.8 43 87.8 45 91.8 PALB2+OTHER* 2 2 0
Evidence of progression n % n % n % OTHER 18 7 11
PSA only 27 27.6 15 30.6 12 24.5 BRCA1+CDK12+
Radiographic PD +/- PSA 71 72.4 34 69.4 37 75.5 1 1 0
OTHER*
Site of metastatic disease n % n % n %
Lung 8 8.2 4 8.2 4 8.2
* More than one aberration
Lymph nodes 66 67.3 34 69.4 32 65.3
Liver 23 23.5 11 22.4 12 24.5
Bone 82 83.7 41 83.7 41 83.7
PSA (ng/ml) – median (Q1-Q3) 154.8 (45.5-472.0) 151.5 (49.0-446.0) 158.0 (45.5-472.0)
RECIST measurable disease
Bone lesions only 10 10.2 5 10.2 5 10.2
Non-measurable disease only
13 13.3 5 10.2 8 16.3
(+/- bone lesions)
Measurable disease (+/- bone
75 76.5 39 79.6 36 73.5
lesions)

57
TH-7635 Exp 29/08/2021
Joaquin Mateo, MD PhD
Results: Primary Endpoint Analyses
• 98 randomized, 92 evaluable for primary endpoint analysis (6 found ineligible/not
evaluable and excluded as per SAP/IDMC).
Dose group
Total (n=92)
300mg (n=46) 400mg (n=46)
resp/n % 95% CI resp/n % 95% CI resp/n % 95% CI

Composite Response (confirmed) 43/92 46.7% 36.3-57.4 18/46 39.1% 25.1-54.6 25/46 54.3% 39.0-69.1
RECIST Response 14/70 20.0% 11.4-31.3 6/37 16.2% 6.2-32.0 8/33 24.2% 11.1-42.3
PSA Response ≥50% 30/89 33.7% 24.0-44.5 13/43 30.2% 17.2-46.1 17/46 37.0% 23.2-52.5
CTC conversion 28/55 50.9% 37.1-64.6 13/27 48.1% 28.7-68.1 15/28 53.6% 33.9-72.5

RECIST / PSA response 32/92 34.8% 25.1-45.4 13/46 28.3% 16.0-43.5 19/46 41.3% 27.0-56.8

Per design, ≥19 “composite responses” needed in either arm to recommend dose à 400 mg BID cohort
meet threshold à biomarker identified in TOPARP-A is considered validated.
58
TH-7635 Exp 29/08/2021
Joaquin Mateo, MD PhD
Results: Secondary Endpoints Analysis
Best change from baseline in PSA (%) Best RECIST change from baseline (%)

Change from baseline in sum of target lesions (%)

100 100

80 80
Best change from baseline in PSA (%)

60 60

40 40

20 20

0 0

-20 -20

-40 -40

-60 -60

-80 -80

-100 -100

300mg 400mg 300mg 400mg

Analyses performed on ITT population (all 98 patients)

59
TH-7635 Exp 29/08/2021
Joaquin Mateo, MD PhD
Results: Secondary Endpoints Analysis
Proportion alive and free of radiographic progression

Radiographic Progression Free Survival

1.0
300 mg
0.9 400 mg
0.8

0.7
Median (Q1-Q3):
0.6 300 mg 5.6 (2.8-9.5) 5 patients still on treatment
400 mg 5.5 (2.8-13.0)
0.5

0.4

0.3

0.2

0.1 300 mg
0.0 400 mg
Dose reduction
0 3 6 9 12 15 18 21 24 27 30 33 36
Months since randomisation Interruption
N.at risk (N.events)
300 mg 49 (13) 35 (15) 20 (6) 12 (5) 6 (2) 4 (3) 1 (0) 1 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39
400 mg 49 (13) 34 (14) 20 (3) 16 (3) 10 (2) 8 (3) 5 (2) 3 (1) 2 (1) 1 (0) 1 (0) 0 (0) 0 Months from Cycle 1 Day 1

Analyses performed on ITT population (all 98 patients)

TH-7635 Exp 29/08/2021

60
Joaquin Mateo, MD PhD
 Results: Primary endpoint per gene subgroup (evaluable n=92)

Group 1: Group 2: Group 3: Group 4: Group 5:

BRCA1/2 (n=30) ATM (n=19) CDK12 (n=20) PALB2 (n=7) Other (n=20)

resp/n % resp/n % resp/n % resp/n % resp/n %

Composite Response (confirmed) 25/30 83.3% 7/19 36.8% 5/20 25.0% 4/7 57.1% 4/20 20.0%
RECIST Objective Response 11/21 52.4% 1/12 8.3% 0/18 0.0% 2/6 33.3% 0/17 0.0%
PSA response ≥50% 23/30 76.7% 1/19 5.3% 0/20 0.0% 4/6 66.7% 2/17 11.8%
CTC conversion 17/22 77.3% 5/10 50.0% 5/12 41.7% 0/2 0.0% 3/11 27.3%

RECIST / PSA response 24/30 80.0% 2/19 10.5% 0/20 0.0% 4/7 57.1% 2/20 10.0%

Non-mutually exclusive subgroups - one patient with BRCA1/2+CDK12+Other mutations and two patients
with PALB2+Other mutations included in analysis for each subgroup separately.

Other mutations – 4 responders with mutations in: BRCA2+CDK12+CHEK2 (CTC response), FANCA (CTC/PSA
response), WRN (CTC response), CHEK2 (PSA response)

61
TH-7635 Exp 29/08/2021
Joaquin Mateo, MD PhD
 Results: Secondary endpoints per gene subgroup (ITT n=98)
Best change from baseline in PSA (%) Best RECIST change from baseline (%)

Change from baseline in sum of target lesions (%)

100 100

80 80
Best change from baseline in PSA (%)

60 60

*
40 40
*

20 20
*
*
0 0

-20 -20

-40 -40

-60 -60

-80 -80

-100 -100

BRCA1/2 ATM CDK12 PALB2 Other BRCA1/2 ATM CDK12 PALB2 Other

Patients with mutations in more than one subgroup are marked in the above figures (*)

62
TH-7635 Exp 29/08/2021
Joaquin Mateo, MD PhD
 Results: Radiographic PFS per gene subgroup (ITT n=98)
Radiographic Progression Free Survival
1.00
aaa N Median (95% CI)
Proportion alive and free of radiographic progression

0.90 BRCA1/2 (32) 8.3 (5.5-13.0)

ATM (21) 5.8 (4.4-10.9)
0.80
CDK12 (20) 2.9 (2.6-5.6)
0.70 PALB2 ( 7) 5.3 (0.4-NE)
Other (18) 2.8 (2.6-4.3)
0.60

0.50 BRCA1/2
0.40 ATM
CDK12
0.30 PALB2
0.20 Other
PSA prog
0.10 Rad Prog
0.00 Clin Prog

0 3 6 9 12 15 18 21 24 27 30 0 3 6 9 12 15 18 21 24 27 30 33 36 39
Months since randomisation Months from Cycle 1 Day 1

*One patient with BRCA1/2+CDK12+Other mutations and two patients with PALB2+Other mutations were analysed in the BRCA1/2 and PALB2, respectively.

63
Joaquin Mateo, MD PhD TH-7635 Exp 29/08/2021
Results: Safety and Tolerability
Treatment-Emergent Adverse Events
(%) Total (N=98) 300mg (N=49) 400mg (N=49)
% G1+ % G3+ % G1+ % G3+ % G1+ % G3+
Anaemia 69.4 33.7 63.3 30.6 75.5 36.7
Fatigue 54.1 7.1 44.9 6.1 63.3 8.2
Back pain 31.6 7.1 34.7 8.2 28.6 6.1 Dose-reductions:
Nausea 30.6 1.0 36.7 2.0 24.5 0.0 • 36.7% at 400mg
Thrombocytopenia 26.5 6.1 22.4 6.1 30.6 6.1 • 12.2% at 300mg
Vomiting 25.5 0.0 20.4 0.0 30.6 0.0
Decreased appetite 25.5 2.0 30.6 4.1 20.4 0.0
Weight decreased 24.5 1.0 18.4 2.0 30.6 0.0 Discontinuations due to AE:
Diarrhoea 20.4 2.0 18.4 2.0 22.4 2.0 • 26.7% at 300mg
Arthralgia 18.4 5.1 18.4 2.0 18.4 8.2 • 10.4% at 400mg
Neutropenia 18.4 5.1 22.4 4.1 14.3 6.1
Hypertension 17.3 5.1 18.4 2.0 16.3 8.2
Dyspnoea 17.3 2.0 12.2 2.0 22.4 2.0
Abdominal pain 16.3 5.1 8.2 0.0 24.5 10.2
Urinary tract infection 15.3 6.1 12.2 6.1 18.4 6.1
Creatinine increased 15.3 0.0 18.4 0.0 12.2 0.0
Oedema peripheral 15.3 1.0 12.2 0.0 18.4 2.0
TH-7635 Exp 29/08/2021 64
Joaquin Mateo, MD PhD
Conclusions:
§ Olaparib has antitumor activity against mCRPC with DDR gene alterations
§ Gene aberration type matters: Response rates and rPFS differ between gene subgroups
‒ BRCA1/2-loss mCRPC: RR ≈ 80% with median rPFS>8 months (>1 year ≈ 1/3) in the post-docetaxel and post-abi/enza
setting
‒ PALB2-mutated mCRPC: Antitumor activity similar to that for BRCA2 (small number)
‒ ATM mutated mCRPC: Antitumor activity observed, although more modest, but with longer rPFS than in remaining
subgroups, but more data are required to understand importance of biological context.

§ Dose may matter, but CDK12 aberrations imbalanced between arms

‒ Composite RR for 400mg, but not 300mg, fulfilled predefined criteria confirming TOPARP-A results
‒ Increased RR and longer benefit with 400mg BID, but 37% dose-reduced to 300mg.

§ Ongoing work: monoallelic vs biallelic, somatic vs germline, and sub-clonality (CTC falls?)
§ Registration trials for PARPi are ongoing in mCRPC based on TOPARP.

TH-7635 Exp 29/08/2021

65
Joaquin Mateo, MD PhD
2020

TH-7635 Exp 29/08/2021

Prostate Cancer: PARP Inhibitors Have Arrived!
§ Since 2019, FDA has approved 2 new PARP inhibitors for use in patients
with prostate cancer: Olaparib and rucaparib
‒ When to use them?
‒ Which patients?
‒ What to expect?

TH-7635 Exp 29/08/2021

 How are PARP Inhibitors Used in Prostate Cancer?
§ PARP inhibitors currently used for treatment of adults with metastatic CRPC
§ Which mutations in DNA repair genes benefit from PARP inhibition?
‒ BRCA2, BRCA1 may be most sensitive; PALB2, ATM may be insensitive; others?[1,2]
‒ Olaparib (PROfound cohort genes):[3] HRR genes, including BRCA
‒ Rucaparib (TRITON2)[4]: BRCA1, BRCA2 only
§ Sequencing
‒ After AR-targeted therapy (eg, abiraterone, enzalutamide): Olaparib
‒ After chemotherapy and AR-targeted therapy: Rucaparib…for now
§ Monotherapy

1. Marshall. Eur Urol. 2019;76:452. 2. Nepomuceno. Int J Mol Sci. 2017;18:1886.

3. Hussain. ESMO 2019. Abstr LBA12_PR. 4. Abida. ESMO 2019. Abstr 846PD. TH-7635 Exp 29/08/2021
 Olaparib in Prostate Cancer
§ FDA approved May 2020 for metastatic CRPC with HRR gene mutations
(germline or somatic)
‒ Previous treatment with enzalutamide or abiraterone
‒ Based on PROFOUND phase III efficacy data (N = 386)
‒ Major efficacy outcome was rPFS
‒ Median rPFS w/BRCA1/2 or ATM mutations: 7.4 mos with olaparib vs 3.6 mos
with enzalutamide or abiraterone
‒ Median rPFS w/any PROFOUND cohort HRR mutation: 5.8 mos with olaparib vs
3.5 mos with enzalutamide or abiraterone
‒ Supported by confirmed ORR, OS outcomes
Olaparib PI. 2020. TH-7635 Exp 29/08/2021
 Phase III PROfound: Olaparib vs Physician’s Choice in
Progressing Metastatic CRPC
Stratified by previous taxane (yes vs no) and
measurable disease (yes vs no)

Olaparib 300 mg BID

Cohort A: BRCA1, (n = 162)
BRCA2, or ATM PD
2:1 Physician’s Choice* by BICR
Patients with mCRPC alterations
(n = 245) (n = 83) Crossover allowed upon
and progression on
progression on physician’s
prior NHA; harboring Olaparib 300 mg BID
Cohort B: Other choice therapy
gene alterations with (n = 162)
a role in HRR alterations 2:1 PD
(N = 387) (n = 142) Physician’s Choice* by BICR
(n = 83)

*Enzalutamide 160 mg QD or abiraterone acetate 100 mg QD plus prednisone 5 mg BID.

†BRCA1/2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RA51D, or RAD54L.
§ Primary endpoint: radiographic PFS in Cohort A using RECIST 1.1 and PCWG3 by BICR
§ Secondary endpoints: radiographic PFS in both cohorts, confirmed radiographic ORR in Cohort A,
time to pain progression in Cohort A, OS in Cohort A
Hussain. ESMO 2019. Abstr LBA12_PR. TH-7635 Exp 29/08/2021
STATISTICAL MULTIPLICITY TESTING PROCEDURE

Statistical assumption for primary endpoint

Primary endpoint
rPFS by BICR in Cohort A
• Target sample size of 240 subjects in Cohort A
(alpha=0.05) • Target hazard ratio = 0.53, 95% power, 2-sided 5%
Confirmed ORR by BICR in alpha (60% maturity, 143 events)
Cohort A
Hierarchical testing

(alpha=0.05)

Key secondary endpoints

Hierarchical testing design
rPFS by BICR in Cohorts A+B • If the primary endpoint demonstrated statistical
(alpha=0.05) significance, the key secondary endpoints were tested
sequentially
Time to pain progression
in Cohort A • A multiple-testing procedure was used to control for the
(alpha=0.05) type 1 error rate

OS in Cohort A OS in Cohort A Patients randomized between Apr 2017 – Nov 2018

Interim Final
(alpha=0.01) (alpha=0.047)
Data cut-off: 4 Jun 2019

TH-7635 Exp 29/08/2021

 PROfound: PFS
BRCA1/2 ATM CDK12
Median PFS, Mos Median PFS, Mos Median PFS, Mos
§ Olaparib: 9.8 HR: 0.22 § Olaparib: 5.4 HR: 1.04 § Olaparib: 5.1 HR: 0.74
§ Control: 3.0 (95% CI: 0.15-0.32) (95% CI: 0.61-1.87) (95% CI: 0.44-1.31)
§ Control: 4.7 § Control: 2.2

1.0 1.0 1.0

Probability of Imaging-Based PFS

0.8 0.8 0.8

0.6 0.6 0.6

0.4 0.4 0.4

Olaparib
Control
0.2 0.2 Control 0.2 Olaparib
Control
0 Olaparib 0
0
0 1 2 3 4 5 6 7 8 910111213141516171819202122 0 1 2 3 4 5 6 7 8 910111213141516171819202122 0 1 2 3 4 5 6 7 8 910111213141516171819202122
Mos Mos Mos

De Bono. NEJM. 2020; 382:2091. TH-7635 Exp 29/08/2021

 PROfound: OS
BRCA1/2 ATM CDK12
Median OS, Mos Median OS, Mos Median OS, Mos
§ Olaparib: 19.1 HR: 0.61 § Olaparib: 17.3 HR: 0.82 § Olaparib: 14.2 HR: 0.65
§ Control: 15.1 (95% CI 0.37-1.01) § Control: 17.9 (95% CI: 0.39-1.88) § Control: 11.5 (95% CI: 0.35-1.25)
1.0 1.0 1.0

0.8 0.8 Olaparib 0.8

Probability of OS

0.6 Olaparib 0.6 Control 0.6

0.4 0.4 0.4

Control Olaparib
0.2 0.2 0.2
Control
0 0 0
0 1 2 3 4 5 6 7 8 91011121314151617181920212223242526272829 0 1 2 3 4 5 6 7 8 91011121314151617181920212223242526272829 0 1 2 3 4 5 6 7 8 91011121314151617181920212223242526272829
Mos Mos Mos

§ 80% of the patients in the control arm “crossed over” to receive olaparib
De Bono. NEJM. 2020; 382:2091. TH-7635 Exp 29/08/2021
 PROfound Subgroup Analysis: Not All Mutations Benefit
Subgroup Subgroup for Progression or Death (95% CI)
All patients 0.49 (0.38-0.63)
Previous taxane use
Yes 0.39 (0.29-0.53)
No 0.77 (0.50-1.22)
81 10.84 (9.17-13.08) Measurable disease at baseline
BRCA2 3.48 (1.74-3.65) Yes 0.41 (0.30-0.56)
47
No 0.64 (0.43-0.98)
61 5.09 (3.61-5.52) Olaparib Metastases at baseline
CDK12 2.20 (1.71- 4.83) Bone only 0.57 (0.35-0.94)
28 Control Visceral 0.42 (0.28-0.64)
Other 0.57 (0.37-0.90)
62 5.36 (3.61-6.21) (95% CI) ECOG score at baseline
ATM 4.70 (1.84-7.26) 0 0.67 (0.46-1.00)
24 1 0.45 (0.32-0.64)
8 2.07 (1.38-5.52) 2 0.31 (0.10-1.13)
BRCA1 Age of randomization
5 1.84 (1.71-3.71) < 65 yrs 0.53 (0.34-0.85)
≥ 65 yrs 0.52 (0.39-0.70)
7 5.59 (1.64-11.99) Region
CHEK2 Asia 0.67 (0.44-1.04)
5 3.35 (1.38-NR)
Europe 0.48 (0.33-0.71)
6 2.69 (1.77-3.91) North and South America 0.43 (0.26-0.73)
PPP2R2A PSA at baseline
4 NR ≥ Median 0.46 (0.33-0.65)
< Median 0.65 (0.44-0.96)
RAD51B 4 10.89 (1.61-14.75) Gene alteration
Frequency

1 1.77 BRCA1 0.41 (0.13-1.39)

BRCA2 0.21 (0.13-0.32)
3 ATM 1.04 (0.61-1.87)
RAD54L 7.20 (3.71-7.39) CDK12 0.74 (0.44-1.31)
2 2.41 (1.81-3.02) CHEK12 0.87 (0.23-4.13)
PPP2R2A 6.61 (1.41-46.41)
0 2 RAD54L 0.33 (0.05-2.54)
4 6 8 10
0.06 0.25 1.00 4.00 16.00
Median Imaging-Based PFS (Mos)
Olaparib better Control better

De Bono. NEJM. 2020; 382:2091. TH-7635 Exp 29/08/2021

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) 0.88 (0.58, 1.36) 0.49 (0.38, 0.63)
P<0.0001 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 33.3 vs 2.3% 3.7 vs 8.3% 21.7 vs 4.5%
Odds ratio (95% CI) 20.86 (4.18, 379.18) Not calculated† 5.93 (2.01, 25.40)
P<0.0001
OS (interim)
Hazard ratio (95% CI) 0.64 (0.43, 0.97) 0.73 (0.45, 1.23) 0.67 (0.49, 0.93)
P=0.0173
Denotes multiplicity-controlled endpoint
* Pre-specified sensitivity analysis
†
N=2 responders each for olaparib vs physician’s choice. TH-7635 Exp 29/08/2021
 PROfound: Safety
Olaparib (n = 256) Control (n = 130)
Adverse Event, n (%) All Grades Grade ≥ 3 All Grades Grade ≥ 3
Any 244 (95) 130 (51) 114 (88) 49 (38)
Anemia 119 (46) 55 (21) 20 (15) 7 (5)
Nausea 106 (41) 3 (1) 25 (19) 0
Fatigue or asthenia 105 (41) 7 (3) 42 (32) 7 (5)
Decreased appetite 77 (30) 3 (1) 23 (18) 1 (< 1)
Diarrhea 54 (21) 2 (< 1) 9 (7) 0
Vomiting 47 (18) 6 (2) 16 (12) 1 (< 1)
Constipation 45 (18) 0 19 (15) 0
Back pain 35 (14) 2 (< 1) 15 (12) 2 (2)
Peripheral edema 32 (12) 0 10 (8) 0
Cough 28 (11) 0 3 (2) 0
Discontinuation due to AE 46 (18) NA 11 (8) NA
Death due to AE 10 (4) NA 5 (4) NA
Intervention interruption due to AE 115 (45) NA 24 (18) NA
Dose reduction due to AE 57 (22) NA 5 (4) NA

De Bono. NEJM. 2020;382:2091. TH-7635 Exp 29/08/2021

 MOST COMMON AEs (≥10% OF PATIENTS IN EITHER ARM) IN COHORTS A+B
Olaparib (N=256) Physician's choice (N=130)
Any 95.3 50.8 37.7 87.7
Anemia* 46.5 21.5 5.4 15.4
Nausea 41.4 1.2 19.2
Fatigue & asthenia 41.0 2.7 5.4 32.3
Decreased appetite 30.1 1.2 0.8 17.7
Diarrhea 21.1 0.8 6.9
Vomiting 18.4 2.3 0.8 12.3
Constipation 17.6 14.6
Back pain 13.7 0.8 1.5 11.5 All grades
Peripheral edema 12.5 7.7 Grade ≥3
Cough 10.9 2.3
All grades
Dyspnea 10.2 2.3 3.1
Grade ≥3
Arthralgia 9.4 0.4 10.8
Urinary tract infection 7.0 1.6 3.8 11.5

100 75 50 25 0 0 25 50 75 100
Adverse events (%)

§ 4.3% pulmonary embolism with olaparib vs 0.8% with physician’s choice; none were fatal
§ No reports of myelodysplastic syndromes or acute myeloid leukemia
*Anemia (46.1%) and decreased Hb (0.4%) TH-7635 Exp 29/08/2021
CONCLUSIONS
• In patients with mCRPC with disease progression on prior NHA, olaparib provided a statistically significant and
clinically meaningful improvement in BICR rPFS compared with physician’s choice of enzalutamide or
abiraterone + prednisone in:

– Patients with alterations in BRCA1, BRCA2 and/ or ATM (primary endpoint)

– The overall population with alterations in any qualifying gene with a direct or indirect role in homologous
recombination repair

• Olaparib improved multiple clinical and patient-reported endpoints (rPFS, ORR, time to pain progression)

– Despite >80% cross-over, at interim analysis olaparib had a favorable trend in OS for patients with alterations in
BRCA1, BRCA2 and/ or ATM (HR=0.64), and in the overall population (HR=0.67)

• Olaparib was well tolerated, with a safety profile generally consistent with that seen in other cancers

• PROfound is the first positive biomarker-selected Phase III study evaluating a molecularly-targeted therapy
in men with mCRPC – and highlights the importance of genomic testing in this population

TH-7635 Exp 29/08/2021

$Title$
$Title$

TH-7635 Exp 29/08/2021

$Title$

TH-7635 Exp 29/08/2021

$Title$
$Title$

TH-7635 Exp 29/08/2021

 Rucaparib in Prostate Cancer
§ FDA approved May 2020 for BRCA-mutated metastatic CRPC
‒ Previous treatment with AR-directed therapy and taxane chemotherapy
‒ Based on TRITON2 phase II response data (N = 115)
‒ Confirmed ORR: 44% (95% CI: 31-57) (n = 62 by RECIST)

§ TRITON3: Ongoing phase III study of rucaparib vs physician’s choice of

therapy in patients with metastatic CRPC associated with HRD
(NCT02975934)
‒ Enrolling with planned N of 400
Rucaparib PI. 2020. TH-7635 Exp 29/08/2021
 TRITON2: Rucaparib in Metastatic CRPC With HRR Gene
Alterations
§ International, multicenter, open-label phase II study
Patients with mCRPC and deleterious
somatic or germline alteration in HRR
genes*; progression on AR-directed tx† Until radiographic
for PC and 1 prior line of taxane-based Rucaparib 600 mg BID progression or
CT for CRPC; no prior PARPi, in 28-d cycles§ discontinuation for
mitoxantrone, cyclophosphamide, or other reason
platinum-based CT; ECOG PS 0/1 *Local or central testing of blood or tumor samples for alterations in HRR genes: BRCA1, BRCA2,
(N = 85‡) ATM, BARD1, BRIP1, CDK12, CHEK2, FANCA, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D,
RAD54L. †Abiraterone, enzalutamide, or apalutamide. ‡Enrollment cutoff: April 16, 2018.
§ Primary endpoints §Assessments: tumor Q8W for 24 wks, then Q12W; PSA Q4W.

‒ Among patients with measurable disease at BL: centrally assessed, confirmed ORR per modified
RECISTǁ/PCWG3
‒ Among patients without measurable disease at BL: locally assessed, confirmed PSA response (≥ 50%
decrease) rate
ǁRECIST modified to include up to 10 target lesions (maximum 5 per site), excluding prostatic bed or bone lesions; MRI permitted.
Abida. ESMO 2018. Abstr 793PD. TH-7635 Exp 29/08/2021
 TRITON2: Baseline Characteristics
Altered HRR Gene
Characteristic BRCA1/2 ATM CDK12 Other* Overall
(n = 45) (n = 18) (n = 13) (n = 9) (N = 85)
Median age, yrs (range) 71 (50-88) 72.5 (62-84) 64 (49-79) 72 (60-86) 71 (49-88)
Race, n (%)
§ White 35 (77.8) 12 (66.7) 6 (46.2) 5 (55.6) 58 (68.2)
§ Black or African American 4 (8.9) 3 (16.7) 1 (7.7) 1 (11.1) 9 (10.6)
§ Unknown 6 (13.3) 3 (16.7) 6 (46.2) 3 (33.3) 18 (21.2)
ECOG PS 0/1/≥ 2, % 35.6/62.2/2.2 55.6/44.4/0 46.2/53.8/0 11.1/77.8/11.1 33.8/58.8/2.4
52.0 59.3 57.7 54.0 54.0
Median PSA, ng/mL (range)
(3.5-4782.0) (9.2-4350.0) (23.3-2966.5) (8.8-798.8) (3.5-4782.0)
Gleason score ≥ 8, n (%) 33 (73.3) 6 (33.3) 13 (100) 6 (66.7) 58 (68.2)
Metastases, n (%)†
§ Bone 40 (88.9) 17 (94.4) 10 (76.9) 7 (77.8) 74 (87.1)
§ Nodal 28 (62.2) 5 (27.8) 11 (84.6) 8 (88.9) 52 (61.2)
§ Visceral 19 (42.2) 4 (22.2) 4 (30.8) 1 (11.1) 28 (32.9)
§ Hepatic 8 (17.8) 2 (11.1) 1 (7.7) 1 (11.1) 12 (14.1)
Germline alteration status, n (%)
§ Yes 15 (33.3) 5 (27.8) 0 0 20 (23.5)
§ No/indeterminate 30 (66.7) 13 (72.2) 13 (100) 9 (100) 65 (76.5)
*Includes n = 2 with FANCA alterations; n = 1 each with BRIP1, CHEK2, NBN, PALB2, RAD51, BRIP1/CHEK2, or CHEK2/CDK12 alteration. †Categories not mutually exclusive.

Abida. ESMO 2018. Abstr 793PD. TH-7635 Exp 29/08/2021

 TRITON2: Radiographic Responses in Evaluable Patients
With BRCA1/2 Alterations
Best Change From BL in Sum of Target Lesions (n = 26†)
100 HRR gene
80 BRCA1/2
60
Change From BL (%)

40
20
0
-20
-40
-60 * * *
Alteration status * * * * *
-80 *
-100 Germline Somatic *
*

Each bar represents a single patient; patients with no change from BL are shown as 0.5% for clarity.
*Confirmed RECIST/PCWG3 response. †Patients with measurable disease at BL and ≥ 1 post-BL scan.

Abida. ESMO 2018. Abstr 793PD. TH-7635 Exp 29/08/2021

 TRITON2: Radiographic Responses in Evaluable Patients
With HRR Gene Alterations
Best Change From BL in Sum of Target Lesions (n = 46†)
100 HRR gene
80 BRCA1/2 ATM
60 CDK12 FANCA
Change From BL (%)

40 BRIP1 Other
20
0
-20
-40
-60 * * ***
*** *
-80 Alteration status **
-100 *
Germline Somatic Not available
*

Each bar represents a single patient; patients with no change from BL are shown as 0.5% for clarity. Threshold for PR (30% decrease from
BL) indicated by dotted line. *Confirmed RECIST/PCWG3 response. †Includes patients with measurable disease at BL and ≥ 1 post-BL scan.

Abida. ESMO 2018. Abstr 793PD. TH-7635 Exp 29/08/2021

 TRITON2: PSA Responses in Evaluable Patients By
Mutation Type
Best PSA Change From BL (n = 84†)
HRR gene
‡§ ¶
100 BRCA1/2 ATM
80 CDK12 FANCA
60 BRIP1 Other
Change From BL (%)

40 Alteration status Measurable disease

20 Germline Somatic NA Yes No
0
-20
-40
-60 ***
*
-80 ** ******
******
-100 ********

Each bar represents a single patient; patients with no change from BL are shown as 0.5% for clarity. Upper dotted line: 50% decrease from BL PSA; lower
dotted line: 90% decrease from BL PSA. *Confirmed PSA response. †Includes patients with ≥ 1 post-BL PSA measurement. ‡231% increase. §183% increase.
¶125% increase.

Abida. ESMO 2018. Abstr 793PD.

89 TH-7635 Exp 29/08/2021
 TRITON2: Any-Grade Treatment-Emergent AEs With
Rucaparib in Regardless of Causality
Overall Safety Population Overall Safety Population
Treatment-Emergent (N = 85) Treatment-Emergent (N = 85)
AE, n (%) AE, n (%)
Any Grade Grade ≥ 3 Any Grade Grade ≥ 3
Asthenia/fatigue 38 (44.7) 4 (4.7) Arthralgia 11 (12.9) 1 (1.2)
Nausea 36 (42.4) 3 (3.5) Dizziness 11 (12.9) 0
Anemia/decreased Hb 24 (28.2) 13 (15.3) Back pain 10 (11.8) 2 (2.4)
Decreased appetite 24 (28.2) 3 (3.5) Peripheral edema 10 (11.8) 0
Constipation 19 (22.4) 1 (1.2) Weight decreased 10 (11.8) 0
ALT/AST increased 18 (21.2) 4 (4.7) Dysgeusia 9 (10.6) 0
Vomiting 17 (20.0) 0 Dyspnea 9 (10.6) 0
Diarrhea 16 (18.8) 1 (1.2) Hematuria 9 (10.6) 3 (3.5)

Abida. ESMO 2018. Abstr 793PD. TH-7635 Exp 29/08/2021

 TRITON3: Rucaparib vs Physician’s Choice Therapy in
Metastatic CRPC With HRR Gene Alterations
§ Randomized, ongoing, multicenter, open-label phase III study
Patients with mCRPC; deleterious
somatic or germline alteration in Rucaparib 600 mg BID
BRCA1/2 or ATM on local or x 28-day cycles Until radiographic progression or
central genomic testing of blood, (n = 267) discontinuation for other reason
archival tumor tissue, or 2:1
Crossover from chemo to
screening tumor tissue; Physician’s Choice*
rucaparib optional following PD
progression on AR-directed tx† for (n = 133)
PC; ECOG PS 0/1; no prior PARPi
or CT for mCRPC *Docetaxel + prednisone 75 mg/m2 in 21-day cycles (max 10 cycles) or abiterone +
(planned N = 400) prednisone 1000 mg QD or enzalutamide 160 mg QD. †Abiraterone, enzalutamide,
or investigational agent. ǁModified RECIST to document soft tissue disease and
PCCTWG v.3 criteria to document radiographic progression of bone lesions.

§ Primary endpoints: radiographic PFS (rPFS) by IRR

Abida. ESMO 2018. Abstr 793PD.

TH-7635 Exp 29/08/2021
 TALAPRO-1: Talazoparib in Metastatic CRPC with DNA
Damage Repair Mutations
§ International phase II study; first interim analysis
Patients with mCRPC and a mono-allelic
or bi-allelic DDR alteration in one of the
following genes: ATM, ATR, BRCA1, Until radiographic
Talazoparib 1 mg/d
BRCA2, CHEK2, FANCA, MLH1, progression or
(0.75 mg for moderate
MRE11A, NBN, PALB2, RAD51C; 1-2 discontinuation for
renal impairment)
prior chemo regimens and progression other reason
on AA/enzalutamide
(N = 81)

§ Primary endpoint: ORR

§ Secondary endpoints: TTR, DOR, PSA decrease ≥ 50%, CTC count conversion, time
to PSA progression, radiographic PFS, OS, safety, PROs, pharmacokinetics

de Bono. ASCO GU 2020. Abstract 119. TH-7635 Exp 29/08/2021

 TALAPRO-1: Efficacy by DDR Subgroup with ≥ 16 Weeks
Treatment

Response, n/N (%) BRCA1/2 PALB2 ATM Other Total

(n = 25) (n = 3) (n = 15) (n = 10) (N = 53)
Composite response 17/25 (68.0) 1/3 (33.3) 1/15 (6.7) 0 (0) 19/53 (35.8)
ORR 10/20 (50) 0 (0) 1/14 (7.1) 0 (0) 11/43 (25.6)
§ CR 2/20 (10) 0 (0) 0 (0) 0 (0) 2/43 (4.7)
§ PR 8/20 (40) 0 (0) 1/14 (7.1) 0 (0) 9/43 (20.9)
PSA ↓≥ 50% from BL 16/25 (64.0) 1/3 (33.3) 1/15 (6.7) 0 (0) 18/53 (34.0)

de Bono. ASCO GU 2020. Abstract 119. TH-7635 Exp 29/08/2021

 TALAPRO-1: Radiographic PFS by DDR Alteration
1.0 X
DDR n Events, Median 95% CI
0.9 X Alteration n PFS, Mos
0.8 XXX
X BRCA1/2 25 9 8.2 5.6-NE
Probability of PFS

0.7 XX PALB2 3 2 4.7 2.0-7.4

X
0.6 X 15
ATM 9 3.5 1.7-8.1
0.5 XX X
Other 10 9 3.2 1.0-3.7
0.4 XX X
0.3
0.2
0.1
0
Patients at
0 3 6 9 12 15
Risk, n PFS Time (Mos)
BRCA1/BRCA2 25 20 7 3 1 0
PALB2 3 1 1 0 0 0
ATM 15 7 2 1 1 1
Other 10 5 1 0 0 0
de Bono. ASCO GU 2020. Abstr 119. TH-7635 Exp 29/08/2021
 TALAPRO-1: Safety
Any TEAE 93.8
79.0
Anemia 44.4
39.5
32.1 All causality
Nausea 19.8
27.2 Adverse drug reaction
Decreased Appetite 18.5
Asthenia 27.2
14.8
Platelet Count Decreased 22.2
21.0
22.2
Constipation 3.7
Neutrophil Count Decreased 18.5
17.3
Fatigue 18.5
12.3
17.3
Peripheral Edema 2.5
16.0
Diarrhea 9.9
Back Pain 16.0
1.2
13.6
Dyspnea 2.5
12.3
Vomiting 3.7
0 20 40 60 80 100
de Bono. ASCO GU 2020. Abstr 119. % TH-7635 Exp 29/08/2021
 GALAHAD: Niraparib in Metastatic CRPC with Biallelic
DNA Repair Defects
§ Ongoing, open-label phase II trial

Patients with mCRPC and DNA repair

defects*; progression on ≥ 1 AR- Treat until PD, toxicity,
directed tx† and ≥ 1 taxane-based CT; no Niraparib 300 mg QD in or death
prior PARPi, or platinum CT; no prior or 28-d cycles
current MDS/AML Follow-up every 3 mos
(N = 165) after end of Tx
*Biallelic alterations in BRCA1/2 (BRCA), ATM, FANCA, PALB2, CHEK2, BRIP1, or HDAC2.

§ Primary endpoint: ORR (RECIST 1.1 criteria) with no evidence of bone progression (PCWG3
criteria)
§ Secondary endpoints: ORR by RECIST 1.1 in patients with biallelic non-BRCA alterations,
circulating tumor cell response, OS, rPFS, duration of objective response, safety
Smith. ESMO 2019. Abstr 3405. TH-7635 Exp 29/08/2021
 GALAHAD: Responses With Niraparib in Patients With
Biallelic BRCA2
Duration of Treatment in All Biallelic DRD (N = 81)
Patients With Response to Niraparib (n = 29) Response, n (%)
BRCA1/2 Non-BRCA
(95% CI)
* (n = 46) (n = 35)
**
Patient Biomarker-Gene Measurable

* 12/29 (41) 2/22 (9)

* ORR
* (23.5-61.1) (1.1-29.2)
*
* PSA50*
24/46 (50) 1/35 (3)
* (34.9-65.1) (0.1-14.9)
* CTC conversion†
18/38 (47) 5/24 (21)
(31.0-64.2) (7.1-42.2)
PR
29/46 (63) 6/35 (17)
* PSA 50% decline CRR
(47.6-76.8) (6.6-33.7)
* CTC conversion
* * Disease progression
Median rPFS, mos
8.2 (5.2-11.1) 5.3 (1.9-5.7)
* (95% CI)
* Treatment ongoing
* BI-BRCA measurable Median OS, mos
12.6 (9.2-15.7) 14.0 (5.3-20.1)
(95% CI)
* BI-BRCA nonmeasurable
*≥ 50% decline in PSA. †CTC conversion from ≥ 5 (unfavorable) to
0 1 2 3 4 5 6 7 8 9 1011121314151617181920212223242526272829 ≤ 5 (favorable) CTCs at least by 28 days.
Mos
Smith. ESMO 2019. Abstr 3405. TH-7635 Exp 29/08/2021
PARP Inhibitors in Prostate Cancer: Early Observations
§ Active drugs, some with long-term activity
§ Response rate: 40% to 60%
§ Primary resistance: 60% to 40%
§ Not one size fits all
Resurgence of “Response Rate”
‒ BRCA2: benefits the most
as an approvability criterion!
‒ ATM: no significant benefit
§ Safety acceptable
‒ Hematologic toxicity
§ May be a model for biomarker-driven targeted therapy
TH-7635 Exp 29/08/2021
 PARP Inhibitors in Clinical Development
Parameter Veliparib Olaparib Rucaparib Niraparib Pamiparib Talazoparib
PARP trapping
- ++ ++ ++ ++ +++
capacity
Single-agent
400 BID 300 BID 600 BID 300 QD 60 BID 1 QD
dose, mg PO
Most frequent Nausea (74%),
Nausea (58% to 76%), Nausea (75%), Nausea (49%),
AEs fatigue (59%), LFT
Nausea (30%), fatigue (29% to 66%), fatigue (69%), Nausea (56%, fatigue (50%),
elevation (36%),
fatigue (25%), vomiting (30% to 37%), vomiting (37%), fatigue (40); headache (33%),
vomiting (34%),
lymphopenia diarrhea (21% to 33%), diarrhea (32%), limited early vomiting (25%),
headache (26%),
(16%) dysgeusia (17%), headache dysgeusia (39%), LFT data alopecia (25%),
insomnia (24%),
(20% to 25%) elevation (34%) diarrhea (22%)
hypertension (19%)
Grade ≥ 3 Thrombocytopenia Anemia (10.3%), Anemia (39%),
Anemia (16% to 19%), Anemia (19%),
hematologic None to date (34%), anemia neutro (8.8%); neutro (21%),
neutropenia (5% to 9%) neutropenia (7%)
AEs (25%), neutro (20%) limited data thrombo (15%)
Clinical OlympiAD (HER2, breast): ARIEL2 (relapsed
benefit PFS (HR: 0.50) ovarian): PFS (HR:
NOVA (relapsed EMBRACA (HER2,
SOLO2 (relapsed ovarian 0.27) Data not
None to date ovarian maint): PFS breast): PFS (HR:
maint): PFS (HR: 0.30) ARIEL3 (relapsed mature; ongoing
(HR: 0.27) 0.54)
SOLO1 (ovarian maint): PFS ovarian maint): PFS
(HR: 0.30) (HR: 0.23)
Approvals None to date Ovarian, breast Ovarian Ovarian None to date Breast (FDA)

Pilié. Clin Cancer Res. 2019;25:3759. TH-7635 Exp 29/08/2021

 PARP Inhibition in Patients With
Metastatic CRPC Without DDR Mutations

TH-7635 Exp 29/08/2021

 PARP Enzymes: Functions Beyond DNA Repair
Functions of PARP-1 § PARP-1 promotes
oncogenic phenotypes
DNA repair Transcriptional modulator in preclinical models of
Single- Double-
prostate cancer
Oncogenes Inflammatory
stranded stranded and tumor genes
repair repair suppressors § PARP-1 is recruited to
ssDNA dsDNA Chromatin modulation the sites of AR and ERG
break break
Gene transcription
binding, and supports
PARP-1 their transcriptional
TF* function
§ Castration-resistant
tumor cells exhibit
increased PARP1 activity
Brenner. Cancer Cell. 2011;19:664. Feng. Mol Cell. 2015;58:925. Haffner. Nat Genet.
2010;42:668. Lin. Cell. 2009;139:1069. Schiewer. Cancer Disc. 2012;2:1134. TH-7635 Exp 29/08/2021
 DNA Repair Deficiency May Improve PFS, PSA
Responses With Abiraterone in Metastatic CRPC
§ NCI 9012: randomized, phase PFS With Abiraterone PSA Decline in Combined Arms
II trial of AA (arm A) vs AA + by DRD Status (n = 32) by DRD Status (n = 80)
veliparib (arm B) in mCRPC 1.0 Median PFS,
DRD
Mos (95% CI)
(N = 153, 148 evaluable)

Probability of PFS
0.8 50 WT
DRD 16.6 (13.5-19.5)
0.6 WT 8.2 (3.9-10.3)
§ Patients whose tumors were

PSA Change (%)

0.4 0
DNA repair deficient (25%; 20 + Censored

of 80 evaluable patients) had 0.2 50%

Log-rank P = .2127 decrease
better, more durable 0
0 3 6 9 12 15 18 21 24 27 30 33 36
-50
90%
responses vs those with WT Pts at risk, n Mos decrease
DNA repair (both arms) DRD 7 7 7 6 1 0 0 0 -100
WT 26 18 15 6 5 3 2 0

Overall DRD DRD WT

Response Rate, %
Arm A (n = 30) Arm B (n = 45) Arm A (n = 7) Arm B (n = 12) Arm A (n = 23) Arm B (n = 33)
Best overall PSA 57 71 86 92 48 64
Measurable disease 43 53 60 90 38 38
PSA RR and measurable disease RR in DRD significantly
Hussain. J Clin Oncol. 2018;36:991. Hussain. ASCO 2016. Abstract 5010. improved vs WT (P = .020 and P = .009, respectively). TH-7635 Exp 29/08/2021
 Synergy Between PARP and AR Signaling
§ Crosstalk between DNA repair and hormone AR antagonist or
abiraterone
signaling: nuclear receptors regulate key DNA
repair factors, which in turn influence nuclear
Nuclear Receptor
receptor function
+
§ In the setting of PARP activity and BER, androgen DNA repair blocked,
receptor is activated dsDNA breaks increased,
synergy with PARPi induced
‒ Drives tumor growth, confers resistance to
DNA repair
hormone therapy factors
‒ Independent of BRCA1 and BRCA2 signaling
Nuclear receptor
§ Important consideration to future development function
of combination strategies
Schiewer. Trends Endocrinol Metab. 2016;27:216. TH-7635 Exp 29/08/2021
 CASPAR: Coinhibition of Androgen Signaling and PARP
in Previously Untreated Metastatic CRPC
§ Randomized, open-label phase III trial

Patients with mCRPC, no prior Rucaparib 600 mg BID +

Treat until
treatments for mCRPC; Enzalutamide 160 mg daily + ADT
PD, then
Prior treatment for mHSPC or long-term
nonmetastatic CRPC; follow up
No screening for mutated HRR Enzalutamide 160 mg daily + ADT
genes required for trial entry

§ Primary endpoint: radiologic PFS

§ Secondary endpoints: OS by HRR mutation status, OS, ORR, safety, QoL (EORTC QOL Questionnaire C30 and
prostate specific 25-item)

§ Correlative endpoints: Prevalence of germline and somatic HRR mutations in previously untreated mCRPC;
prevalence of AR aberrations pre- and post-therapy; prevalence of HRR reversion mutations post-therapy in
PARP inhibitor arm; prevalence of “BRCAness” or NEPC transcriptional signature, or SLFN11 expression in
tumor-derived exosomes and archival tissue
Alliance for Clinical Trials in Oncology. TH-7635 Exp 29/08/2021
Phase II Trial: Olaparib + Abiraterone vs Placebo +
Abiraterone for Metastatic CRPC Following
Chemotherapy

TH-7635 Exp 29/08/2021

 Olaparib + Abiraterone in mCRPC: Background
§ Olaparib: PARP inhibitor approved by FDA for treatment of recurrent ovarian
cancer and previously treated, germline BRCA-mutated advanced ovarian cancer or
metastatic breast cancer[1]
§ In phase II TOPARP-A trial, olaparib monotherapy demonstrated antitumor activity
in patients with previously treated mCRPC, particularly those with DNA-repair
defects[2]
§ Combination of olaparib + abiraterone may provide synergistic antitumor activity
due to increased sensitivity to PARP inhibition resulting from functional HRR
impairment via ADT[3-5]
§ Current study evaluated efficacy, safety of olaparib + abiraterone in patients with
mCRPC following chemotherapy regardless of HRR mutation status[6]
1. Olaparib [package insert]. 2. Mateo J, et al. N Engl J Med. 2015;373:1697-1708. 3. Schiewer MJ, et al. Cancer Discov.
2012;2:1134-1149. 4. Polinghorn WR, et al. Cancer Discov. 2013;3:1245-1253. 5. Asim M, et al. Nat Commun.
2017;8:374. 6. Clarke N, et al. ASCO 2018. Abstract 5003. TH-7635 Exp 29/08/2021
 Olaparib + Abiraterone in mCRPC: Study Design
§ Randomized, double-blind, placebo-controlled phase II trial

Patients with mCRPC,

pretreated with docetaxel, Olaparib 300 mg BID + Abiraterone 1000 mg QD
≤ 2 prior lines of (n = 71)
chemotherapy, Until PD
no previous second-generation
Placebo + Abiraterone 1000 mg QD
antihormonal agents
(n = 71)
(N = 142)

§ Primary endpoint: radiologic PFS

§ Secondary endpoints: rPFS by HRRm status, PFS2, OS, ORR, TFST/TSST,
CTC-conversion rate, HRQoL, safety/tolerability
Clarke N, et al. ASCO 2018. Abstract 5003. TH-7635 Exp 29/08/2021
 Olaparib + Abiraterone in mCRPC: Patient Population
Olaparib + Olaparib +
Abiraterone Abiraterone
Characteristic Abiraterone Characteristic Abiraterone
(n = 71) (n = 71)
(n = 71) (n = 71)
Median age, yrs (IQR) 70 (65-75) 67 (62-74) Extent of disease, n (%)
33 (46) 33 (46)
White race, n (%) 67 (94) 67 (94) § Bone only
8 (11) 11 (15)
§ Soft tissue only
ECOG PS, n (%) 30 (42) 27 (38)
§ Bone and soft tissue
§0 34 (48) 38 (54)
§1 36 (51) 30 (42) Number of bone
§2 1 (1) 1 (1) metastases, n (%)
§ 0-4 32 (45) 46 (65)
Median PSA § 5-9 39 (55) 25 (35)
concentration, μg/L 86 (23-194) 47 (21-199)
(IQR) Prior cabazitaxel
10 (14) 9 (13)
Median time from treatment, n (%)
diagnosis to first dose, 62 (38-93) 48 (32-76) Median duration of prior
mos (IQR) 53 (32-84) 37 (28-59)
LHRH agonist, mos (IQR)

Clarke N, et al. ASCO 2018. Abstract 5003. TH-7635 Exp 29/08/2021

 Olaparib + Abiraterone in mCRPC: Investigator-Assessed
Radiologic PFS (Primary Endpoint)
Olaparib +
1.0 Abiraterone
Abiraterone
Proportion of Patients Event Free
(n = 71)
(n = 71)
0.8 Events, n (%) 46 (65) 54 (76)
Median rPFS, mos 13.8 8.2
0.6

0.4

0.2 HR: 0.65

(95% CI: 0.44-0.97; P = .034)
0.0
0 3 6 9 12 15 18 21 24 27 30
Patients at Risk, n Time from Randomization (Mos)
Olaparib + abiraterone 71 58 50 42 33 26 21 18 13 8 0
Abiraterone 71 48 39 25 21 19 16 14 10 7 0
Clarke N, et al. ASCO 2018. Abstract 5003. Reproduced with permission. TH-7635 Exp 29/08/2021
 HRR mutation testing
Patients with Patients with successful Patients with a
samples test result detected mutation
BRCA2
ATM
Tumor 68 38 3 tHRRm CHEK2
BRCA2
ATM
ATM
CHEK2
Germline 102 102 7 gHRRm PALB2
BRCA2
Prioritized BRCA2
for testing* BRCA2
BRCA2
Plasma 136 96 91 13 ctHRRm ATM
ATM x2
ATM
136 (96%) ATM
142 21 (15%)
Overall randomized
biomarker
HRRm
BRIP1
CDK12 x2
data CDK12
*No valid tumor test result (unless HRRm detected by germline test) CDK12
tHRRm, tumor HRRm; gHRRm, germline HRRm; ctHRRm, circulating-tumor HRRm CHEK1

11
Noel Clarke, ChM FRCS TH-7635 Exp 29/08/20210
 Olaparib + Abiraterone in mCRPC: Radiologic PFS by
HRR Mutation Status
HRR Mutated (n = 21) HRR Partially Characterized (n = 86) HRR Wild Type (n = 35)
Proportion of Patients Event Free

1.0 Patients, Median 1.0 Patients, Median 1.0 Patients, Median

n rPFS, Mos n rPFS, Mos n rPFS, Mos
0.8 O + A 11 17.8 0.8 O + A 45 0.8 O + A 15 15.0
13.1
A 10 6.5 A 41 A 20 9.7
6.4
0.6 0.6 0.6

0.4 0.4 0.4

0.2 HR: 0.74 0.2 HR: 0.67 0.2 HR: 0.52

(95% CI: 0.26-2.12; P = .58) (95% CI: 0.40-1.13; P = .13) (95% CI: 0.24-1.15; P = .11)
0.0 0.0 0.0
0 6 12 18 24 30 0 6 12 18 24 30 0 6 12 18 24 30
Mos From Randomization

§ HRR mutation testing completed on 142 patients with tumor, germline, or plasma samples
‒ Biomarker data obtained for 136 patients (96%), 21 (15%) of which were HRR mutation positive
‒ HRR mutations included BRCA2, ATM, CHEK1, CHEK2, PALB2, BRIP1, CDK12

Clarke N, et al. ASCO 2018. Abstract 5003. Reproduced with permission. TH-7635 Exp 29/08/2021
 Olaparib + Abiraterone in mCRPC: Other Secondary
Endpoints
Response § ORR: 27% with combination vs 32%
abiraterone alone
Olaparib +
48%
50 Abiraterone 47%
§ Median DoR extended with
Abiraterone combination olaparib + abiraterone
40
32%
‒ 17.8 vs 12.1 mos with abiraterone
Patients (%)

30 27%
alone
21% 21%
20 § PFS2, OS did not differ significantly
between arms
10
0 0 ‒ HR for PFS2: 0.79; P = .28
0
CR PR SD PD ‒ HR for OS: 0.91; P = .66
§ 50% CTC conversion rate with
combination, 46% with abiraterone
alone
Clarke N, et al. ASCO 2018. Abstract 5003. Reproduced with permission. TH-7635 Exp 29/08/2021
 Olaparib + Abiraterone in mCRPC: Safety

Olaparib + Abiraterone Abiraterone

Outcome, n (%)
(n = 71) (n = 71)
Any AE 66 (93) 57 (80)
Grade ≥ 3 AE 38 (54) 20 (28)
Serious AE 24 (34) 13 (18)
Fatal AE 4 (6) 1 (1)
AE leading to dose interruption 24 (34) 9 (13)
AE leading to dose reduction 13 (18) 0
AE leading to discontinuation 21 (30) 7 (10)

§ Median duration olaparib + abiraterone: 309 vs 253 days; median

duration abiraterone: 338 vs 253 days
Clarke N, et al. ASCO 2018. Abstract 5003. TH-7635 Exp 29/08/2021
 Olaparib + Abiraterone in mCRPC: Adverse Events
Olaparib + Abiraterone (n = 71) Abiraterone (n = 71)
10% 10%
Nausea 27 1 2 15 All grades
Anemia 22 15 1 Grade ≥ 3
Back pain 18 1 1 14
Constipation 18 8
Asthenia 16 3 10
Fatigue 15 1 2 9
Vomiting 15 2 1 9
Peripheral edema 13 8
Decreased appetite 12 1 5
Diarrhea 11 1 8
Cough 11 2 2

Serious CV AEs 7* 1†

*n = 4, MI; n = 1 each, fatal cardiac failure, chronic cardiac failure, fatal ischemic stroke. †n = 1, thrombotic stroke.

Clarke N, et al. ASCO 2018. Abstract 5003. Reproduced with permission. TH-7635 Exp 29/08/2021
 Olaparib + Abiraterone in mCRPC: Conclusions
§ In patients with mCRPC previously treated with docetaxel, addition of
olaparib to abiraterone significantly increased radiologic PFS vs
abiraterone alone
‒ HR: 0.65 (95% CI: 0.44-0.97; P = .034)
‒ Benefit seen regardless of HRR mutation status
§ Increased toxicity with combination, including serious cardiovascular
AEs
§ Phase III trial planned, starting in 2018

Clarke N, et al. ASCO 2018. Abstract 5003. TH-7635 Exp 29/08/2021

PARP Inhibition in Prostate Cancer: Thoughts on Moving
Forward
§ 15% to 25% of metastatic CRPCs harbor alterations in DNA repair genes
§ PARP inhibitors “work” in prostate cancer, but how well depends on patient selection
‒ BRCA2, BRCA1 may be most sensitive
‒ ATM may be insensitive
‒ Selection of biallelic genes? Probably not necessary.

§ A lot of work ahead

‒ Selection
‒ Resistance
‒ Combinations
‒ Non-HRD setting
‒ Other factors
TH-7635 Exp 29/08/2021
Thank you