1) The document discusses PARP inhibition in breast cancer, from preclinical rationale to clinical trials. It summarizes key trials like OlympiAD and EMBRACA which showed improved progression-free survival with PARP inhibitors olaparib and talazoparib in advanced BRCA-mutated breast cancer. 2) It also discusses the OlympiA trial, which is evaluating olaparib as adjuvant therapy in early-stage high-risk BRCA-mutated breast cancer patients to reduce the risk of disease recurrence. 3) Finally, it briefly touches on the increased rates of BRCA testing post the "Angelina Jolie effect" and the need to expand BRCA testing

1. PARP Inhibition in Ca Breast : Lab to bedside
Dr. Muzammil Shaikh
Director
Department of Medical oncology
Nanavati Max Institute of Cancer care

2. The impact on BRCA testing “Angelina Jolie gene” and
“Angelina Jolie effect”
2
http://healthland.time.com/2013/05/14/angelina-jolies-double-mastectomy-what-we-know-about-brca-mutations-and-breast-
cancer/
James et al, MJA, 2016, Leide et al Br Ca Res Treat 2018, J Lee et al J Breast Cancer. 2017 etc…..
* Kmietowicz Z. BMJ 2016;355:i6702
• 40 publications documenting pivotal change in behaviors
• Increased patients inquiry for BRCA related cancer
• Increase in referral for testing
• Increased self funded BRCA testing
• A 64% increase in BRCA testing rates occurred in the 15
business days after the editorial was published*
• Increased option for bilateral mastectomies as prevention in
both carriers and non carriers

3. BRCAm prevalence in unselected breast cancer is approximately 5%1-7
Individual studies in unselected* BC populations report varying frequencies of BRCAm1-7
Only a few studies have actively looked at BRCAm rates. Variability may be due to the method of analysis, and
whether populations have founder mutations or not
of breast cancer
patients will have a
BRCAm
Prevalence of BRCA1/2 mutation in unselected BC populations
Women with BC unselected for family history or age of onset
CI=confidence interval; BRCAm=BRCA mutation; BC=breast cancer
1. Høberg-Vetti et al. Eur J Hum Genetic, 2016; 2. Gomes et al. Breast Cancer Res Treatment, 2007; 3. Hernandez JE et al. Hered Cancer Clin Pract, 2014; 4. Bu et al. Int J Cancer
2016 139, 1091–1097; 5. Abugattas J et al. Clin Genetics, 2015; 6. Kim R et al SABCS 2017 poster P5-08-28; 7. Winter et al. Ann Oncol. 2016 Aug; 27(8): 1532–1538

4. 4
Mittal et al. Annals of surgical oncology 2021. https://doi.org/10.1245/s10434-021-10870-w, Rajagopal, T., Seshachalam, A., Jothi, A. et al. Mol Biol Rep (2022). https://doi.org/10.1007/s11033-022-07129-2
The prevalence of pathogenic mutations in breast cancer patients is
higher in Indian patients compared with most other populations.
Data are available to suggest that 50–80% of individuals at risk of
having a hereditary breast cancer are never tested as they do not
meet the current criteria.
Among the 59 TNBC genomic DNA samples sequenced,
BRCA mutations were identified in 8 (13.6% ) patients.
BRCA1 mutations in 6 patients, and BRCA2 mutations in 2 patients.
BRCA Mutations In Context of Indian Patients

5. NCCN criteria for BRCA testing for hereditary risk in
individuals diagnosed with breast cancer
5
1. NCCN Clinical Practice Guidelines. Genetic/ Familial High Risk Assessment: Breast, Ovarian, Pancreatic V1 2022.
as accessed on 20.3.2022
≤45
years
≤50
years
>51
years
Any age
BRCA
testing
Additional breast
cancer primary*
Family history criteria
Family history criteria
• Aid in systemic treatment decision for
using PARPi : Metastatic setting
• Aid in adjuvant treatment decision with
Olaparib in High risk HER2-ve BC
• Triple Negative breast cancer (TNBC)
• Personal/Family History criteria
• Male Breast Cancer
• Ethnicity associated with higher
mutation frequency e.g. Ashkenazi
Jewish
Individual
diagnosed
with breast
cancer
Personal history criteria

6. PARP inhibition: Concept of Synthetic Lethality
6

7. PARPi exploit synthetic lethality in tumour cells with
dysfunctional homologous recombination repair1-4
1. Helleday et al. Molecular Oncology 2011 5,387-393, 2. Aly A et al. J Mol Cell Biol. 2011, 3, 66-74, 3. Girolimetti et al. Biomed Research International. 2014;
4. O’Connor MJ. Mol Cell 2015;60:547–560 DSB – Double Strand Breaks; HRR – Homologous Recombination Repair
In tumour cells with defective HRR, accumulation of cytotoxic DSBs lead to cell death1
Single strand break
PARP
Normal cell
Repair by base
excision repair
PARP enzyme required to repair
single strand DNA breaks
Homologous recombination (HR)
repairs double strand DNA breaks
Double strand break
Normal cell
Repair by homologous
recombination
7

8. 1. Helleday et al. Molecular Oncology 2011 5,387-393, 2. Aly A et al. J Mol Cell Biol. 2011, 3, 66-74, 3. Girolimetti et al. Biomed Research International. 2014;
4. O’Connor MJ. Mol Cell 2015;60:547–560
Single strand break
PARP
Double strand breaks
Homologous recombination
deficient cancer cell
Increase in double
strand breaks
Cell death
Non-functioning HR
PARP inhibitor
PARPi exploit synthetic lethality in tumour cells with
dysfunctional homologous recombination repair1-4
In tumour cells with defective HRR, accumulation of cytotoxic DSBs lead to cell death1
8

9. PARP INHIBITION IN ADVANCED BREAST CANCER
9

10. OlympiAD study design
BICR, blinded independent central review; ER, oestrogen receptor; HRQoL, health-related quality of life;
PR, progesterone receptor; RECIST, response evaluation criterial in solid tumours; TNBC, triple negative breast cancer
*No evidence of progression during treatment in the advanced setting or ≥12 months since (neo)adjuvant treatment
10
Primary endpoint
Progression-free survival (RECIST
1.1, BICR)
Treat
until
progression
Target Population
• HER2-negative metastatic breast
cancer
– ER+ and/or PR+ or
– TNBC
• gBRCAm
• Prior chemotherapy
• anthracycline and taxane
• ≤2 chemotherapy lines in
metastatic setting
• HR+ disease progressed on
≥1 endocrine therapy, or not
suitable
• Prior platinum use*
2:1 randomization
Chemotherapy treatment
of physician’s choice
(TPC)
• Capecitabine
• Eribulin
• Vinorelbine
Olaparib
300 mg tablets bd
Key 2nd endpoints
Secondary endpoints
• Time to second progression
or death
• Overall survival
• Objective response rate
• Safety and tolerability
• Global HRQoL
(EORTC-QLQ-C30)
M Robson et al. N. Engl. J. Med. 2017 10;377(6):523–33

11. Primary endpoint: PFS by BICR
11
PFS
(%)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
0
20
40
60
80
100
177
63
154
44
107
25
94
21
69
11
40
8
23
4
21
4
11
1
4
1
3
1
2
1
1
0
0
0
At risk, n 205
97
Olaparib
TPC
Months
BICR: blind independent centralised review - FAS; Maturity rate: 234/302=77%
Stratified log rank test, stratified by previous chemotherapy for MBC (yes/no) and HR+ versus TNBC. 2 sided p value
M Robson et al. N. Engl. J. Med. 2017 10;377(6):523–33
Patients in the Olaparib arm showed a 42 % reduction in risk of progression or
death compared to the physicians choice of chemotherapy arm.
The curves separated early and the PFS benefit was sustained beyond 2 months of therapy
Olaparib TPC
n 205 97
Events (%) 163 (79.5%) 71 (73.2%)
Median (m)
7.0 4.2
HR = 0.58
95 % CI (0.43,0.80) p=0.0009
PFS free at 6m (%) 54.1 32.9
PFS free at 12m (%) 25.9 15.0
Median Duration of
Follow up (m)
14.5 14.1

12. EMBRACA: Talazoparib vs Chemotherapy in Advanced BRCA1/2-
Positive, HER2-Negative Breast Cancer
Randomized, open-label phase III study conducted at 145 sites in 16
countries
Primary endpoint: PFS by BICR
Secondary endpoints: ORR, OS, safety,
Investigational endpoints: DoR, QoL
Litton. NEJM. 2018;379:753.
Patients with HER2-negative LA/MBC
with deleterious or suspected
deleterious germline BRCA1/2 mutation;
previous anthracycline and/or taxane,
≤ 3 previous lines of CT* for adv disease
(N = 431)
Until PD or
unacceptable AEs
Talazoparib 1.0 mg PO QD
(n = 287)
Physician’s Choice of Chemotherapy†
(n = 144)
Stratified by HR status (ER+ and/or PgR+ vs TNBC), prior chemo
regimens (0 vs ≥ 1), history of CNS metastases (yes vs no)
21-day
cycles
*Previous platinum-based therapy for EBC permitted if DFI ≥ 6 mos
†Physician’s choice of: capecitabine 1250 mg/m2 PO BID Days 1-14;
eribulin 1.4 mg/m2 IV Days 1, 8; gemcitabine 1250 mg/m2 IV Days 1, 8; or
vinorelbine 30 mg/m2 IV Days 1, 8, and 15.

13. Median follow-up time: 11.2 mos
EMBRACA: PFS by BICR (Primary Endpoint)
Litton. NEJM. 2018;379:753. Litton. AACR 2020. Abstr CT071.
PFS Outcome
Talazoparib
(n = 287)
Standard
CT
(n = 144)
PFS events, % 186 (65) 83 (58)
Median PFS,
mos (95% CI) 8.6 (7.2-9.3) 5.6 (4.2-6.7)
HR (95% CI) 0.54 (0.41-0.71); P < .001
1-yr PFS, % 37 20
Mos
0 42
3 6 12 15 18 21 24 27 30 33 36 39
9
10
0
90
80
70
60
50
40
30
20
10
0
PFS
(%)
Talazoparib
Standard therapy
 No OS advantage for talazoparib vs CT; findings consistent across all prespecified subgroups

14. PARP Inhibitors:
Tolerance Profiles of Olaparib and Talazoparib
1. Robson. Ann Oncol. 2019;30:58. 2. Litton et al. Annals of Oncology. 2020(31);11:1-10.Supplementary.
Adverse Event, % Olaparib (OlympiAD)[1] Talazoparib (EMBRACA)[2]
Grade ≥ 3 serious
AE
38 (vs 50 TPC) 28.3 (vs 27.0 TPC)
 Anemia
16.1 39.2
 Neutropenia
9.3 20.9
 Thrombocytope

15. ESMO Clinical Practice Guideline for the diagnosis, staging and treatment
of patients with metastatic breast cancer
Gennari A et al on behalf of the ESMO Guidelines Committee, ESMO Clinical Practice Guideline for the
diagnosis, staging and treatment of patients with metastatic breast cancer† , Annals of Oncology (2021).

16. ESMO Clinical Practice Guideline for the diagnosis, staging and treatment
of patients with metastatic breast cancer
Gennari A et al on behalf of the ESMO Guidelines Committee, ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer† , Annals of Oncology (2021).

17. PARP INHIBITION IN EARLY BREAST
CANCER

18. Patients with BRCAm early breast cancer have distinct tumour
characteristics compared with the sporadic population1–5
18
1. Baretta Z, et al. Medicine. 2016;95:e4975; 2. Becourt S, et al. J Clin Oncol. 2018;36(suppl; abstr e13522); 3. Aleskandarany M, et al. Breast Cancer Res Treat. 2015;150:81–90; 4. Song Y, et al. Cancer. 2020;126(2):271–280; 5.
Valachis A, et al. Breast Cancer Res Treat. 2014;144:443–455; 6. Force J, et al. Presented at SABCS 2018. 4–8 December. San Antonio, TX. Abstract P3-08-07; 7. Quek R, et al. J Clin Oncol. 2018;36(suppl; abstr e12575);
8. Liu M, Wang S. Presented at SABCS 2019. 10–14 December. San Antonio, TX. Abstract P3-08-51
BRCAm breast cancer is characterised by a more aggressive phenotype than sporadic disease1
More CNS
metastases in
patients with
BRCAm BC4
More
contralateral /
ipsilateral
disease5
BRCAm tmours
are of higher
grade than
sporadic
tumours3
Patients are
diagnosed at
younger age2
Patients with
BRCAm BC may
have higher risk
of recurrence6-8

19. PARPi clinical trials in neoadjuvant setting in breast cancer
19
Goncalves A et al. Cancers 2020, 12, 1378

20. OlympiA: phase III study of olaparib versus placebo as
adjuvant treatment for high risk gBRCA-mutated, HER2-
negative BC
20
A CPS+EG score incorporates pretreatment clinical stage, oestrogen receptor status, nuclear grade and pathological stage after neoadjuvant chemotherapy
B by STEEP system2
1. NEJM OlympiA; 2.Hudis CA. J Clin Oncol 2007;25:2127–32
Randomization
1:1
N=1836
• DDFS
• OS
• BRCA1/2 associated
cancers
• Health related QoL
• Safety and tolerability
• IDFSb
Primary endpoints
Key secondary endpoints
Eligibility
• Germline pathogenic or
likely pathogenic BRCA1 or
BRCA2 mutation
• Stage II-III breast cancer
• HER2-negative
(HR-positive or TNBC)
• Completed local treatment
and ≥ six cycles of
neoadjuvant or adjuvant
chemotherapy containing
anthracyclines and/or
taxanes
Olaparib 300 mg
BID
(n=921)
Placebo
(n=915)
Twice daily
Neoadjuvant group
• TNBC: non-pCR
• HR-positive: non-pCR and CPS+EG score ≥3a
Neoadjuvant
chemotherapy
Surgery RT as required
Stratification factors
• HR-positive vs. TNBC
• Neoadjuvant vs. adjuvant
• Prior platinum-based chemotherapy (yes vs. no)
1 years’ treatment
4 high-risk patient populations
Adjuvant group
• TNBC: ≥pT2 or ≥pN1
• HR-positive: ≥4 positive lymph nodes
Adjuvant
chemotherapy
Surgery
RT/surgery
as required

21. 1/19/2022
21
https://www.uptodate.com/contents/practice-changing-updates?search=olympia&source=search_result&selectedTitle=2~4&usage_type=default&display_rank=2#H11_131821
(Accessed on September 21, 2021)., Mittendorf EA et al. J Clin Oncol. 2011;29:1956-1962.,
Tutt ANJ et al. Supplementary Appendix N Engl J Med. 2021. DOI: 10.1056/NEJMoa2105215. Accessed June 21, 2021.
aStage according to AJCC.
CPS + EG score provides a more refined prognostic categorization of patients with
breast cancer after neoadjuvant chemotherapy versus clinical or pathological
stage alone.
Stagea/Feature Points
Clinical Stage 0
IIA
IIB
IIIA
IIIB
IIIC
0
0
1
1
2
2
Pathologic Stage 0
I
IIA
IIB
IIIA
IIIB
IIIC
0
0
1
1
1
1
2
Receptor status ER receptor-
negative
1
CPS + EG score = sum of
the point scores of
clinical stage +
pathological stage +
oestrogen receptor
status + nuclear grade

22. Olaparib reduced the risk of invasive recurrence or death by 42% vs
placebo
22 *Kaplan–Meier estimates; †Stratified Cox proportional hazards model; 99.5% CIs are shown for the HR because p<0.005 was required to indicate statistical significance for this endpoint.
Tutt ANJ et al. N Engl J Med. 2021. DOI: 10.1056/NEJMoa2105215. Accessed June 3, 2021
3-year IDFS rate*
Olaparib
(n=921)
Placebo
(n=915)
85.9%
77.1%
Difference 8.8%
95% CI 4.5–13.0
921 820 737 607 477 361 276 183
915 807 732 585 452 353 256 173
Olaparib
Placebo
0 6 12 18 24 30 36 42
Months since randomization
0
20
40
60
80
100
Invasive
disease-free
survival
(%)
Olaparib (106 events)
Placebo (178 events)
88.4%
93.3%
81.5%
89.2%
85.9%
77.1%
No. at risk
HR 0.58†
99.5% CI 0.41–0.82
p<0.0001
1-year
treatment cap
Primary endpoint: invasive disease-free survival (ITT)
IDFS

23. 87.5% of patients treated with adjuvant olaparib were free of distant
recurrence or death at 3 years
23 †Non-proportional hazards; 99.5% CI is shown for the HR for DDFS because p<0.005 was required to indicate statistical significance for this endpoint
Tutt ANJ et al. N Engl J Med. 2021. DOI: 10.1056/NEJMoa2105215. Accessed June 3, 2021
921 823 744 612 479 364 279 187
915 817 742 594 461 359 263 179
Olaparib
Placebo
0 6 12 18 24 30 36 42
Months since randomization
0
20
40
60
80
100
Distant
disease-free
survival
(%)
Olaparib (89 events)
Placebo (152 events)
90.2
94.3
83.9
90.0 87.5
80.4
No. at risk
1-year
treatment cap
Secondary endpoint: distant disease-free survival
3-year DDFS rate
Olaparib
(n=921)
Placebo
(n=915)
87.5%
80.4%
Difference 7.1%
95% CI, 3.0‒11.1
HR 0.57 †
99.5% CI, 0.39‒0.83
P<0.0001
DDFS

24. ADVERSE EVENTS OF ANY GRADE ≥ 10%
Grade 1
Grade 2
Grade ≥ 3
Nausea
Fatigue
Anaemia
Vomiting
Headache
Diarrhoea
57% 24%
40% 27%
24% 4%
23% 8%
20% 17%
18% 14%
Neutropaenia 16% 7%
Leukopaenia
Decreased appetite
16%
13%
6%
6%
4%
12%
11% 7%
Dysgeusia
Dizziness
Arthralgia 10% 13%
0 20 40
60 40 20
Adverse events, %
*Number presented only where at least 1% in either arm have a grade 3 AE
60
Grade ≥ 3*
Tutt A et al. Presented at ESMO Virtual Plenary. 16 March 2022. VP1-2022
Olaparib Placebo
(2%)
(9%)
(5%)
(3%)

25. OlympiA Implication: Identify gBRCA1/2m carriers with early-
stage breast cancer
• Identify gBRCA1/2m carriers with early-stage breast cancer
• Genetic testing is necessary to make treatment decisions, not just to manage future
cancer risks
• Less than 50% with breast cancer who qualify by NCCN criteria are being offered
genetic testing
• Underutilization greatest in minority and underserved populations
25
Presented by Nadine Tung in ASCO 2021

26. Summary
• PARP inhibitors are a welcome addition to the treatment arsenal for patients
with locally advanced or metastatic gBRCA-mutated, HER2-negative BC.
• The safety & HRQoL profiles are more favorable than chemotherapy agents.
• The most common AEs observed during treatment with PARP inhibitors are
generally manageable, but patients should be monitored regularly.
• New directions for evaluation of PARP inhibitors include earlier stages of BC
and in combination with agents that target other HRR-related pathways, with
a view to potentially avoiding resistance to PARP inhibitor therapy and
expanding indications beyond the gBRCA-mutated population.
Cortesi L et al. Targeted Oncology (2021) 16:255–282