Rol de la terapia dirigida IPARP en el tratamiento adyuvante del

carcinoma de mama temprano RH + HER2

CARLOS ALBERTO CALDERON
ONCOLOGO CLINICO
HOSPITAL INTERNACIONAL DE COLOMBIA
CONFLICTO DE INTERESES
• ADVISORY BOARD : ROCHE, PFIZER, ELI LILLY INTERAMERICA,
NOVARTIS
• SPEAKER TRAINING: ELI LILLY INTERAMERICA, NOVARTIS , PFIZER,
ASTRAZENECA, ROCHE, MSD
• PROTOCOLOS DE INVESTIGACION: MSD, NOVARTIS, AMGEN, ELI LILLY
INTERAMERICA.
Avances en screening y tratamientos han
mejorado la sobrevida en cáncer de mama

Hendrick RE, et al. Cancer.2019;125(9)1482:1488

 Avances en screening y tratamientos han
mejorado la sobrevida en cáncer de mama

The New USPSTF Mammography Recommendations — A Dissenting View, Steven Woloshin, M.D., Karsten Juhl Jørgensen, M.D., D.Med.Sci., Shelley Hwang, M.D., M.P.H., and
H. Gilbert Welch, M.D., M.P.H. n engl j med 389;12 nejm.org September 21, 2023
Escenario complejo
Pronóstico post-neoadyuvancia
Pronóstico post-adyuvancia
Necesidad Insatisfecha
Prevalencia de BRCA en Cáncer de mama

Armstrong N, et al. Clin Epidemiol.2019;11:543-561

Fenotipo en pacientes BRCAm
Tumores BRCA RH+
 Over a quarter of people with early breast cancer will have their cancer
return1

9%

Breast cancer is the

20–30%* will recur ~9% with HER2-negative
most common where cure is no longer
disease have a gBRCAm5,6
cancer worldwide2 possible1,3,4
“No copiar y/o difundir de forma integral"
*Of patients diagnosed with early breast cancer

1. Riggio AI, et al. Br J Cancer. 2021;124(1):13-26 1 2. Sung H, et al. CA Cancer J Clin. 2021;71:209–249 3. Caswell-Jin J, et al. JNCI Cancer Spectrum (2018) 2(4): pky062 4. 2014 Review of Cancer Medicines on the WHO List of Essential
Medicines: Early stage breast cancer. Accessed November 2021. 5. De Talhouet S, et al. Sci Rep. 2020;10:7073 6. Winter C, et al. Ann Oncol. 2016;27:1532–1538: Supplementary Appendix
 Detection of a germline BRCAm significantly impacts a patient’s
care plan
Germline BRCAm breast cancer

Many patients do not meet

Patients with gBRCA mutations are
gBRCA status can alter surgical common gBRCA testing criteria*
often younger and present with
decisions and therapeutic options4 and may miss the opportunity to
aggressive disease1-3
benefit from targeted treatment5

The OlympiA trial investigates olaparib as an adjuvant therapy for patients with gBRCAm, HER2-negative eBC
who have a high risk of recurrence despite standard of care local and systemic therapy

*Such as family history or age of diagnosis

1. Baretta Z, et al. Medicine. 2016;95:e4975. 2. Aleskandarany M, et al. Breast Cancer Res Treat. 2015;150:81–90. 3. Becourt S, et al. J Clin Oncol. 2018;36(suppl; abstr e13522). 4. Tung N & Garber. Brit J Can. 2018;119:141–152.;
5. Rummel S, et al. Cancers. 2020;12:234.
Herramientas

Intensidad de dosis

Platinos

Inmunoterapia

Capecitabine

iPARP
OlympiA: phase III study of olaparib versus placebo as adjuvant treatment for
high risk gBRCA-mutated, HER2-negative BC

Neoadjuvant group
Eligibility • TNBC: non-pCR Olaparib 300 mg Primary endpoints
• HR-positive: non-pCR and CPS+EG score ≥3a BID
• Germline pathogenic
(n=921)
BRCA1 or BRCA2 mutation Neoadjuvant • IDFSc
Surgery RT as required
chemotherapy
• Stage II-III breast cancer
• HER2-negative Randomization
(HR-positive or TNBC) 4 high-risk patient populations 1:1 Key secondary endpoints
N=1836
• Completed local treatment • DDFS
and ≥ six cycles of Adjuvant group
• TNBC: ≥pT2 or ≥pN1 Placebob • OS
neoadjuvant or adjuvant • HR-positive: ≥4 positive lymph nodes
chemotherapy containing (n=915) • BRCA1/2 associated
Twice daily cancers
anthracyclines and/or Adjuvant RT/surgery
Surgery
taxanes chemotherapy as required • Health related QoL
1 years’ treatment • Safety and tolerability

Stratification factors
• HR-positive vs. TNBC
• Neoadjuvant vs. adjuvant
• Prior platinum-based chemotherapy (yes vs. no)

aCPS+EG score incorporates pretreatment clinical stage, oestrogen receptor status, nuclear grade and pathological stage after neoadjuvant chemotherapy
bData to support adjuvant capecitabine was not available when the OlympiA study was initiated in 2014
cby STEEP system2
1. NEJM OlympiA; 2.Hudis CA. J Clin Oncol 2007;25:2127–32
Baseline characteristics were well balanced between treatment groups
Olaparib Placebo
n=921 n=915

Age – years, median (interquartile range), years 42 (36–49) 43 (36–50)

Female, n (%) 919 (99.8) 911 (99.6)

BRCA gene affected in germline, n (%)

BRCA1 657 (71.3) 670 (73.2)
BRCA2 261 (28.3) 239 (26.1)
BRCA1 & BRCA2 2 (0.2) 5 (0.5)
Missing 1 (0.1) 1 (0.1)

Menopausal status (females only), n (%)

Premenopausal 572/919 (62.2) 553/911 (60.7)
Postmenopausal 347/919 (37.8) 358/911 (39.3)
Bilateral invasive breast cancer, n (%)
No 881 (95.7) 888 (97.0)
Yes 40 (4.3) 27 (3.0)

Tutt ANJ et al. N Engl J Med. 2021. DOI: 10.1056/NEJMoa2105215. Accessed June 3, 2021
 Baseline characteristics were well balanced between treatment groups
Olaparib Placebo
n=921 n=915
Prior (neo)adjuvant chemotherapy, n (%)a
Adjuvant 461 (50.1) 455 (49.7)
Neoadjuvant 460 (49.9) 460 (50.3)
Anthracycline and taxane regimen Protocol amendment 871 (94.6) 849 (92.8)
Anthracycline regimen (without taxane) 7 (0.8) 13 (1.4)
Taxane regimen (without anthracycline) 43 (4.7)
The original protocol activated in 2014 was developed 52 (5.7)
for patients with HER2-negative disease but included
(Neo)adjuvant platinum-based chemotherapy , n (%) with TNBC following a regulatory review.
only patients
No 674 (73.2) 677 (74.0)
Yes 247 (26.8)
The first patient with HR-positive disease was enrolled in 238 (26.0)
December 2015.
HR status, n (%)b
HR-positive / HER2-negative 168 (18.2) 157 (17.2)
TNBC c
751 (81.5) 758 (82.8)

Concurrent hormone therapy (HR-positive only), n/N (%) 146/168 (86.9) 142/157 (90.4)

a7 patients in the Olaparib arm and 15 patients in the placebo arm received less than 6 cycles of (neo)adjuvant chemotherapy. Regimen for 1 patients in the placebo arm was not
reported. All reported as protocol deviations; bDefined by local test results; cTNBC: ER- and PgR-negative defined as IHC nuclear staining <1% AND HER2-negative (not eligible for
anti-HER2 therapy) defined as IHC 0, 1+ without ISH OR IHC 2+ and ISH non-amplified with ratio <2.0 and, if reported, average HER2 copy number <4 signals/cell OR ISH non-
amplified with ratio <2.0 and, if reported, average HER2 copy number <4 signals/cell (without IHC). Two patients were excluded from the summary of the TNBC subset because they
did not have a confirmed HER2-negative status

Tutt ANJ et al. N Engl J Med. 2021. DOI: 10.1056/NEJMoa2105215. Accessed June 3, 2021
 Majority of patients have higher grade tumours
Olaparib Placebo
n=921 n=915
Grade, n (%)a
Gx: cannot be assessed 11/714 (1.5) 7/720 (1.0)
G1: well differentiated 2/714 (0.3) 3/720 (0.4)
G2: moderately differentiated 128/714 (17.9) 114/720 (15.8)
G3: poorly differentiated/undifferentiated 562/714 (78.7) 582/720 (80.8)
Not done 11/714 (1.5) 14/720 (1.9)
Pathological AJCC stage (adjuvant chemotherapy only), n (%)b
IAc 5/461 (1.1) 2/455 (0.4)
IB 15/461 (3.3) 11/455 (2.4)
IIA 264/461 (57.3) 250/455 (54.9)
IIB 70/461 (15.2) 75/455 (16.5)
IIIA 73/461 (15.8) 70/455 (15.4)
IIIB 0 2/455 (0.4)
IIIC 28/461 (6.1) 41/455 (9.0)

aIncludes only those patients receiving neoadjuvant chemotherapy for whom the electronic case report form indicates histological grade was assessed on treatment-naïve core biopsy and on all patients receiving adjuvant
chemotherapy; b These include two occult breast cancer (placebo, n=2), six pTx (olaparib, n=4; placebo, n=2) and two pNx (olaparib, n=2); c Reported as protocol deviations

Tutt ANJ et al. Supplementary Appendix N Engl J Med. 2021. DOI: 10.1056/NEJMoa2105215. Accessed June 3, 2021
 Pathological characteristics (CPS+EG score by HR status)
Olaparib Placebo
n=921 n=915
CPS+EG score (neoadjuvant chemotherapy only), n (%)
CPS+EG score of 2, 3 or 4 398/460 (86.5) 387/460 (84.1)
CPS+EG score of 5 or 6 22/460 (4.8) 15/460 (3.3)

HR-positive/HER2-negative, n (%)
CPS+EG score ≤2a 13/460 (2.8) 6/460 (1.3)
CPS+EG score of 3 or 4 88/460 (19.1) 85/460 (18.5)
CPS+EG score of 5 or 6 3/460 (0.7) 1/460 (0.2)

TNBC, n (%)b
CPS+EG score ≤2 151/460 (32.8) 144/460 (31.3)
CPS+EG score of 3 or 4 179/460 (38.9) 197/460 (42.8)
CPS+EG score of 5 or 6 19/460 (4.1) 14/460 (3.0)
Not recorded 7/460 (1.5) 13/460 (2.8)

a Reported as protocol deviations; b Data for 7 patients in the Olaparib arm and 13 patients in the placebo arm was missing

Tutt ANJ et al. Supplementary Appendix N Engl J Med. 2021. DOI: 10.1056/NEJMoa2105215. Accessed June 3, 2021.
Olaparib reduced the risk of invasive recurrence or death by 42%
vs. placebo
Primary endpoint: invasive disease-free survival (ITT)
IDFS at DCO1‡
93.3%
100
89.2%
85.9%
88.4%
HR 0.58†
Invasive disease-free survival (%)

80
81.5% 99.5% CI 0.41–0.82
77.1%
1-year
p<0.0001
60 treatment cap

40 3-year IDFS rate*

Olaparib
20 (n=921) 85.9%
Olaparib (106 events)
Placebo (178 events)
Placebo
0
(n=915) 77.1%
0 6 12 18 24 30 36 42
No. at risk
Months since randomization Difference 8.8%
Olaparib 921 820 737 607 477 361 276 183
95% CI 4.5–13.0
Placebo 915 807 732 585 452 353 256 173

*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; ‡DCO1 27 March 2020 (at 284 IDFS events,
15% data maturity)

Tutt ANJ et al. N Engl J Med. 2021. DOI: 10.1056/NEJMoa2105215. Accessed June 3, 2021
IDFS benefit associated with olaparib was maintained with
1-year additional follow-upƗ
Exploratory Analysis
IDFS at DCO2‡
93.4%
100
89.7%
86.1% 82.7%
88.4% HR 0.63
Invasive disease-free survival (%)

80
81.4%
77.3% 95% CI 0.50–0.78
1-year 75.4%
60 treatment cap

40 4-year IDFS rate

Olaparib
20 (n=921) 82.7%
Olaparib (134 events)
Placebo (207events)
Placebo
0
(n=915) 75.4%
0 6 12 18 24 30 36 42 48 54
No. at risk
Months since randomization Difference 7.3%
Olaparib 921 825 777 738 694 603 495 382 293 204
95% CI 3.0–11.5
Placebo 915 807 765 715 656 571 459 370 293 187

ƗIDFS analysis is descriptive at OS IA2; ‡DCO2 12 July 2021 (at 330 IDFS events, 25% data maturity)

Tutt J, Garber J, Gelber R, et al. Pre-specified event driven analysis of Overall Survival in the OlympiA Phase III trial of adjuvant olaparib in germline BRCA1/2 mutation associated breast cancer. [Presentation]. Presented at ESMO
Virtual Plenary; March 16-18, 2022.
Olaparib demonstrated a significant OS benefit with 90% of
patients alive at 4-years in the olaparib arm
Secondary endpoint: overall survival
98.0% OS at DCO2
100 95.0% 92.8% 89.8%

96.9% HR 0.68†
92.8%
80 89.1% 86.4% 98.5% CI 0.47–0.97
p=0.009
Overall survival (%)

1-year
60 treatment cap

40 4-year OS rate
Olaparib
20 (n=921) 89.8%
Olaparib (75 events)
Placebo (109 events)
Placebo
0
(n=915) 86.4%
0 6 12 18 24 30 36 42 48 54
No. at risk
Months since randomization Difference 3.4%
Olaparib 921 862 844 809 773 672 560 437 335 228
95% CI -0.1–6.8
Placebo 915 868 843 808 752 647 530 423 333 218

*Data from the pre-specified second interim analysis of OS (at ~330 IDFS events); cut-off date July 2021 (DCO2), data maturity 9%; †Non-proportional hazards; 98.5% CI is shown for the HR for OS because p<0.015 is required to
indicate statistical significance for this endpoint
1. Tutt A, Garber J, Gelber R, et al. Pre-specified event driven analysis of Overall Survival in the OlympiA Phase III trial of adjuvant olaparib in germline BRCA1/2 mutation associated breast cancer. [Presentation]. Presented at ESMO
Virtual Plenary; March 16-18, 2022 2. In House Data, AstraZeneca. Data on file SD-2020-ALL-0088
Over 7% more patients treated with adjuvant olaparib were free of
distant recurrence or death at 3 years vs. placebo
Secondary endpoint: distant disease-free survival
DDFS at DCO1‡
100 94.3%
90.0% 87.5%
HR 0.57†
Distant disease-free survival (%)

90.2%
80 83.9%
80.4%
99.5% CI, 0.39‒0.83
1-year
P<0.0001
60 treatment cap

40 3-year DDFS rate

Olaparib
20 (n=921) 87.5%
Olaparib (89 events)
Placebo (152 events) Placebo
0
(n=915) 80.4%
0 6 12 18 24 30 36 42
No. at risk
Months since randomization Difference 7.1%
Olaparib 921 823 744 612 479 364 279 187
95% CI, 3.0‒11.1
Placebo 915 817 742 594 461 359 263 179

†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; ‡DCO1 27 March 2020 (at 284 IDFS events, 13% maturity)

Tutt ANJ et al. N Engl J Med. 2021. DOI: 10.1056/NEJMoa2105215. Accessed June 3, 2021
Longer follow-up confirms DDFS benefit of adjuvant olaparib vs placebo with
over 7% more patients free of distant recurrence at 4 years
Exploratory Analysis
DDFS at DCO2‡
100 94.4%
90.6% 88.0% 86.5%
HR 0.61
Distant disease-free survival (%)

80 90.3%
84.0%
81.0% 79.1% 95% CI, 0.48‒0.77
1-year
60 treatment cap

40 4-year DDFS rate

Olaparib
20 (n=921) 86.5%
Olaparib (107 events)
Placebo (172 events)
Placebo
0
(n=915) 79.1%
0 6 12 18 24 30 36 42 48 54
No. at risk
Months since randomization Difference 7.4%
Olaparib 921 828 784 746 698 609 501 391 302 209
95% CI, 3.6‒11.3
Placebo 915 818 777 728 670 582 471 379 300 193

ƗDDFS analysis is descriptive at second OS interim analysis; ‡DCO2 12 July 2021 (at 330 IDFS events, 15% maturity)

Tutt A, Garber J, Gelber R, et al. Pre-specified event driven analysis of Overall Survival in the OlympiA Phase III trial of adjuvant olaparib in germline BRCA1/2 mutation associated breast cancer. [Presentation]. Presented at ESMO
Virtual Plenary; March 16-18, 2022.
Incidence of second primary non-breast cancers was halved in patients
who received olaparib vs. placebo
Fewer patients in the olaparib arm had a CNS recurrence vs. the placebo arm
Olaparib N=921 Placebo N=915

Number of patients with a first IDFS events, n (%)*‡ 134 (14.5) 207 (22.6)
Distant recurrence, n (%) 88 (9.6) 136 (14.9)
Distant CNS recurrence 24 (2.6) 38 (4.2)
Distant excluding CNS recurrence 64 (6.9) 98 (10.7)
Regional (ipsilateral) recurrence 9 (1.0) 18 (2.0)
Local (ipsilateral) recurrence 9 (1.0) 12 (1.3)

Contralateral invasive breast cancer 15 (1.6) 18 (2.0)

Second primary non-breast malignancies 11 (1.2) 23 (2.5)
Ovarian 1 (0.1) 6 (0.7)
Peritoneal 0 (0.0) 0 (0.0)
Fallopian tube 1 (0.1) 4 (0.4)
Other 9 (1.0) 13 (1.4)
Deaths without a prior IDFS event† 2 (0.2) 0

*If two recurrence events are reported within 2 months of each other this is referred to as a simultaneous event and will be considered as a single event. In this situation the worst case will be taken as the event ‘type’ but the date
of recurrence will be the earliest date of the two events. †The two deaths without a prior IDFS event were a cardiac arrest and cause unknown; ‡DCO2 12 July 2021

1. Tutt ANJ et al. Supplementary Appendix N Engl J Med. 2021. DOI: 10.1056/NEJMoa2105215. Accessed June 3, 2021. 2 Tutt A, Garber J, Gelber R, et al. Pre-specified event driven analysis of Overall Survival in the OlympiA Phase III
trial of adjuvant olaparib in germline BRCA1/2 mutation associated breast cancer. [Presentation]. Presented at ESMO Virtual Plenary; March 16-18, 2022.
A consistent benefit was seen across all IDFS subgroups (DCO2)
Stratified hazard ratio for invasive P value for
Subgroup Olaparib Placebo
disease-free survival (95% CI) heterogeneity
No. of patients with an invasive-
disease event/total no.

All patients 134 / 921 207 / 915 0.628 (0.504, 0.779) NA

Prior chemo
Adjuvant 46 / 461 75 / 455 0.618 (0.425, 0.888) 0.977
Neoadjuvant 88 / 460 132 / 460 0.622 (0.473, 0.813)

Prior platinum
Yes 42 / 247 51 / 238 0.791 (0.523, 1.187) 0.197
No 92 / 674 156 / 677 0.575 (0.443, 0.742)

HR status
HR-positive/HER2-negative 25 / 168 34 / 157 0.680 (0.402, 1.134) 0.754
TNBC 109 / 751 173 / 758 0.620 (0.487, 0.787)

BRCA
BRCA1 83 / 579 149 / 588 0.533 (0.406, 0.695)
0.615
BRCA2 34 / 235 44 / 216 0.693 (0.440, 1.082)
BRCA1 and BRCA2 0/2 0/3 NC

0.25 0.50 0.75 1.00 1.25

Favours olaparib Favours placebo
The size of the blue squares corresponds to the number of events contributing to the estimate of the treatment effect (i.e., proportional to square root of 1/variance of the estimated hazard ratio). There was no statistical evidence
of heterogeneity between any subgroup and the ITT IDFS treatment effect. DCO2 12 July 2021

Tutt A, Garber J, Gelber R, et al. Pre-specified event driven analysis of Overall Survival in the OlympiA Phase III trial of adjuvant olaparib in germline BRCA1/2 mutation associated breast cancer. [Presentation]. Presented at ESMO
Virtual Plenary; March 16-18, 2022.
A consistent benefit was seen across all DDFS subgroups (DCO2)
Stratified hazard ratio for distant P value for
Subgroup Olaparib Placebo
disease-free survival (95% CI) heterogeneity
No. of patients with an distant-
disease event/total no.

All patients 107 / 921 172 / 915 0.607 (0.476, 0.771) NA

Prior chemo
Adjuvant 33 / 461 59 / 455 0.562 (0.363, 0.855) 0.698
Neoadjuvant 74 / 460 113 / 460 0.623 (0.463, 0.832)

Prior platinum
Yes 36 / 247 43 / 238 0.812 (0.519, 1.263) 0.132
No 71 / 674 129 / 677 0.540 (0.403, 0.719)

HR status
HR-positive/HER2-negative 23 / 168 31 / 157 0.692 (0.399, 1.182) 0.608
TNBC 84 / 751 141 / 758 0.591 (0.450, 0.772)

BRCA
BRCA1 66 / 579 118 / 588 0.544 (0.400, 0.732) 0.927
BRCA2 28 / 235 41 / 216 0.609 (0.373, 0.979)
BRCA1 and BRCA2 0/2 0/3 NC

0.25 0.50 0.75 1.00 1.25

Favours olaparib Favours placebo
The size of the blue squares corresponds to the number of events contributing to the estimate of the treatment effect (i.e., proportional to square root of 1/variance of the estimated hazard ratio). There was no statistical evidence
of heterogeneity between any subgroup and the ITT IDFS treatment effect. DCO2 12 July 2021

Tutt A, Garber J, Gelber R, et al. Pre-specified event driven analysis of Overall Survival in the OlympiA Phase III trial of adjuvant olaparib in germline BRCA1/2 mutation associated breast cancer. [Presentation]. Presented at ESMO
Virtual Plenary; March 16-18, 2022.
OS benefit is derived across all subgroups (DCO2)
P value for
Subgroup Olaparib Placebo Stratified hazard ratio for OS (95% CI)
heterogeneity
No. of patients who died
/total no.

All patients 75 / 921 109 / 915 0.678 (0.503, 0.907) NA

Prior chemo
Adjuvant 22 / 461 28 / 455 0.783 (0.444, 1.365) 0.543
Neoadjuvant 53 / 460 81 / 460 0.638 (0.449, 0.900)

Prior platinum
Yes 27 / 247 29 / 238 0.882 (0.520, 1.491) 0.236
No 48 / 674 80 / 677 0.601 (0.417, 0.855)

HR status
HR-positive/HER2-negative 16 / 168 17 / 157 0.897 (0.449, 1.784) 0.381
TNBC 59 / 751 92 / 758 0.640 (0.459, 0.884)

BRCA
BRCA1 49 / 579 75 / 588 0.643 (0.446, 0.918)
0.845
BRCA2 16 / 235 28 / 216 0.521 (0.276, 0.951)
BRCA1 and BRCA2 0/2 0/3 NC

0.25 0.50 0.75 1.00 1.25

Favours olaparib Favours placebo
The size of the blue squares corresponds to the number of events contributing to the estimate of the treatment effect (i.e., proportional to square root of 1/variance of the estimated hazard ratio). There was no statistical evidence
of heterogeneity between any subgroup and the ITT IDFS treatment effect. DCO2 12 July 2021

Tutt A, Garber J, Gelber R, et al. Pre-specified event driven analysis of Overall Survival in the OlympiA Phase III trial of adjuvant olaparib in germline BRCA1/2 mutation associated breast cancer. [Presentation]. Presented at ESMO
Virtual Plenary; March 16-18, 2022.
SEGURIDAD
 >70% of patients completed treatment according to protocol without the
need for a dose reduction
Olaparib Placebo
n=921 n=915
Completed treatment per protocol, n (%)1* 656 (71.2) 697 (76.2)

Olapariba Placeboa
n=911 n=904

Patients with no dose reduction, n (%)2* 683 (75.0) 857 (94.8)

Number of patients with a dose reduction, n (%)2*

1 dose reduction 170 (18.7) 40 (4.4)
2 dose reductions 57 (6.3) 7 (0.8)
3 or more dose reduction 1 (0.1) 0 (0.0)
Reason for reduction, n (%)2,b*
Adverse event 222 (24.4) 35 (3.9)
Dosing error 6 (0.7) 10 (1.1)
Administrative reasons 2 (0.2) 1 (0.1)
Other 0 (0.0) 1 (0.1)
a Safety analysis set (n=911 in olaparib arm and n=904 in placebo arm). 21 patients who did not received study treatment (n=10 in olarpib arm and n=11 in placebo arm) were excluded from the safety analysis set.

b Reasons for dose reductions are not mutually exclusive for patients with multiple reductions although are counted only once per category.

*DCO1 27 March 2020

1. In House Data. AstraZeneca Pharmaceuticals LP. Data on file. SD-2020-ALL-0077; 2. Tutt ANJ et al. Supplementary Appendix N Engl J Med. 2021. DOI: 10.1056/NEJMoa2105215. Accessed June 3, 2021
 ~10% of patients discontinued treatment due to adverse event

Olaparib Placebo
n=921 n=915

Patients who did not complete study treatment, n (%)* 236 (25.6) 187 (20.4)

Reasons for treatment discontinuation, n (%)*

Adverse event 97 (10.5) 41 (4.5)
Death 1 (0.1) 0 (0.0)
Recurrence of disease 40 (4.3) 80 (8.7)
Lost to follow-up 2 (0.2) 1 (0.1)
Patient decision 84 (9.1) 42 (4.6)
Other reason* 12 (1.3) 18 (2.0)

The most common treatment-emergent AEs that led to discontinuation

of olaparib were nausea (2.0%) and anaemia (1.8%)

*Other reasons for discontinuation of treatment include: for olaparib – site error (n=8), surgery (n=2), investigator's decision (n=1), patient has lost insurance and could no longer come in for the study treatment (n=1), patient was
waiting to initiate investigational product (never started) and then was diagnosed with second primary (n=1); for placebo – site error (n=14), surgery (n=2), treating investigator's decision (n=1), patient had a chronic infection that
did not resolve for months following her registration to the study (n=1)

*DCO1 27 March 2020

Tutt ANJ et al. Supplementary Appendix N Engl J Med. 2021. DOI: 10.1056/NEJMoa2105215. Accessed June 3, 2021
AEs were mostly mild and moderate in the olaparib arm
Olaparib Placebo
n=911 n=904
AE, n (%)*¶
Any AE 836 (91.8) 758 (83.8)
Serious AE 79 (8.7) 78 (8.6)
AESI† 31 (3.4) 51 (5.6)
MDS/AML 2 (0.2) 3 (0.3)
Pneumonitis 9 (1.0) 12 (1.3)
New primary malignancy 21 (2.3) 36 (4.0)
Grade ≥3 AE 223 (24.5) 102 (11.3)
Grade 4 AE‡ 17 (1.9) 4 (0.4)
AE leading to permanent discontinuation of treatment 98 (10.8) 42 (4.6)
AE leading to death§ 1 (0.1) 2 (0.2)

*Safety analysis set (n=911 in olaparib arm and n=904 in placebo arm). 21 patients who did not receive study treatment (n=10 in olarpib arm and n=11 in placebo arm) were excluded from the safety analysis set . Includes AEs with
an onset date on or after the first dose date and up to and including 30 days following date of last dose of study medication; †Includes AESI with onset at any date after first dose of treatment. One patient in the olaparib arm had
both pneumonitis and a non-melanoma skin malignancy and is counted in both categories; ‡Eighteen grade 4 AEs were reported in 17 patients assigned to olaparib; one patient had both grade 4 anaemia and neutropenia. Grade 4
AEs include neutropenia (olaparib, n=5); anaemia (olaparib, n=4); leukopenia (olaparib, n=3); AML, bipolar disorder, fatigue, febrile neutropenia, hepatic function abnormal and suicide attempt (olaparib, n=1 for each); depression
(placebo, n=2); aspartate aminotransferase increased, cholecystitis acute (placebo, n=1 for each); §AEs leading to death are cardiac arrest (olaparib, n=1), AML (placebo, n=1), and ovarian cancer (placebo, n=1); ¶DCO2 12 July 2021

1.Tutt ANJ et al. N Engl J Med. 2021. DOI: 10.1056/NEJMoa2105215. Accessed June 3, 2021 2. Tutt A, Garber J, Gelber R, et al. Pre-specified event driven analysis of Overall Survival in the OlympiA Phase III trial of adjuvant olaparib in
germline BRCA1/2 mutation associated breast cancer. [Presentation]. Presented at ESMO Virtual Plenary; March 16-18, 2022. “No copiar y/o difundir de forma integral"
 Adverse events observed were consistent with other trials of olaparib
AEs of any grade occurring in at least 10% of patientsƗ
Olaparib Placebo
Nausea 57 24

Fatigue 40 (2) 27

Anaemia 24 (9) 4
Anaemia was the only
Vomiting 23 8 Grade 3 AE occurring in
Headache 20 17 Grade 1 more than 5% of
Diarrhoea patients
18 14 Grade 2
Neutropenia 16 (5) 7 Grade ≥3*
Leukopenia 16 (3) 6 Grade 1
Decreased appetite 13 6
Grade 2
Dysgeusia 12 4
Grade ≥3
Dizziness 11 7

Arthralgia 10 13

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

*Number presented only where at least 1% have grade 3 AE ; †DCO2 12 July 2021

34 Tutt A, Garber J, Gelber R, et al. Pre-specified event driven analysis of Overall Survival in the OlympiA Phase III trial of adjuvant olaparib in germline BRCA1/2 mutation associated breast cancer. [Presentation]. Presented at ESMO
Virtual Plenary; March 16-18, 2022.
Blood transfusions were infrequently required*
Majority of patients required only one blood transfusion

Olaparib Placebo
n=921 n=915

Patients with at least one blood transfusion, n (%) 53 (5.8) 8 (0.9)

With ≥ grade 3 anemia on treatment 42 (4.6) 2 (0.2)
With < grade 3 anemia on treatment 9 (1.0) 2 (0.2)
No anemia reported on treatment 2 (0.2) 4 (0.4)
Number of patients with only 1 transfusion, n (%) 37 (4.1) 6 (0.7)
Number of patients with 2 transfusions, n (%) 13 (1.4) 2 (0.2)
Number of patients with 3 or more transfusions, n (%) 3 (0.3) 0 )0.0)

*DCO1 27 March 2020

Tutt ANJ et al. Supplementary Appendix N Engl J Med. 2021. DOI: 10.1056/NEJMoa2105215. Accessed June 3, 2021
CPS & EG staging system is a prognostic assessment tool for early breast
cancer

CPS + EG score provides a more refined prognostic categorization of patients with breast cancer after neoadjuvant
chemotherapy versus clinical or pathological stage alone.

It incorporates pre-treatment clinical stage, pathological stage, oestrogen receptor status, and nuclear grade.

Mittendorf EA et al. J Clin Oncol. 2011;29:1956-1962.

Calculation of CPS & EG score

Stagea/Feature Points
Clinical Stage 0 0
IIA 0
IIB 1
IIIA 1
IIIB 2
IIIC 2
Pathologic Stage 0 0
I 0
IIA 1
IIB 1
IIIA 1
IIIB 1
IIIC 2
Receptor status ER receptor-negative 1
CPS + EG score = sum of
Nuclear grade Nuclear grade 3 1 the point scores of
clinical stage +
Total score (0-6) pathological stage +
oestrogen receptor
status + nuclear grade

a Stage according to AJCC.

Tutt ANJ et al. Supplementary Appendix N Engl J Med. 2021. DOI: 10.1056/NEJMoa2105215. Accessed June 21, 2021.
CALIDAD DE VIDA
 One year of adjuvant olaparib maintained global health status HRQoL vs.
placebo

Patients treated with neoadjuvant chemotherapy Patients treated with adjuvant chemotherapy
100 100

80 80

GHQ score
GHQ score

Better QoL
Better QoL

60 60

40 40

20 Olaparib 20 Olaparib
Placebo Placebo
0 Treatment period
0 Treatment period

Baseline 6 12 18 24 Baseline 6 12 18 24
Time since randomization (months) Time since randomization (months)
1,533 patients were analysed for GHQ; 744 were in the neoadjuvant chemotherapy group and 791 were in the adjuvant chemotherapy group.

*Global Health Quality (GHQ) score ranges from 0 to 100, higher score indicates better QoL. Adjusted least-square mean responses and 95% CI for time points other than baseline are obtained from mixed model for repeated measures
analysis of the GHQ score. The model includes treatment, time and treatment by time interaction, corresponding baseline score, and the baseline score by time interaction.

1. Tutt ANJ et al. Supplementary Appendix N Engl J Med. 2021. DOI: 10.1056/NEJMoa2105215. Accessed June 3, 2021. 2. Ganz PA, et al. Presented at SABCS 2021. 7–10 December. San Antonio, TX.
 There was no clinically meaningful change in fatigue severity across the
duration of the study
Fatigue was the primary PRO endpoint

FACIT-Fatigue Score* - Change from baseline

Improved 4 Neoadjuvant 4
Adjuvant
3
fatigue 3
Average FACIT-Fatigue scale score

Average FACIT-Fatigue scale score

2 2
(change from baseline)

(change from baseline)

1 ‡ ‡ ‡
‡ 1
0 0
-1 -1
Placebo Placebo
-2 -2
Olaparib Olaparib
-3 -3
Worsened Treatment period Treatment period
-4 -4
fatigue 6 months 12 months 18 months 24 months 6 months 12 months 18 months 24 months
Months from randomization Months from randomization

*FACIT-Fatigue score interpretation: ranges from 0-52; a higher score means less fatigue; negative change scores indicate more fatigue; Pre-specified clinically-meaningful difference is 3 points. ‡P-value <0.05

Ganz PA, et al. Presented at SABCS 2021. 7–10 December. San Antonio, TX.
 The clinically meaningful difference in nausea and vomiting with olaparib vs.
placebo was small and resolved after treatment cessation
There was no clinically meaningful change in diarrhoea QoL score between olaparib and placebo
EORTC QLQ-C30 Nausea and Vomiting Score*- Change from baseline

Average nausea and vomiting symptom scale score

Average nausea and vomiting symptom scale score
10
Neoadjuvant 10
Adjuvant
‡§ ‡§ ‡§
8 8
Worsened
6 6

(change from baseline)

nausea/vomiting
(change from baseline)

4 4

2 2

0 0

-2 -2

-4 -4
Placebo Placebo
Improved -6 -6
Olaparib Olaparib
nausea/vomiting -8
Treatment period
-8
Treatment period
-10 -10
6 months 12 months 18 months 24 months 6 months 12 months 18 months 24 months
Months from randomization Months from randomization

EORTC QLQ-C30 diarrhoea Score† -Change from baseline

Neoadjuvant 10 Adjuvant
10
Average diarrhoea symptom scale score

Average diarrhoea symptom scale score

8
8
Worsened 6
6
(change from baseline)

(change from baseline)

4
diarrhoea 4
2
2
0
0
-2
-2
-4
-4 Placebo
Improved -6
Placebo -6
Olaparib
Olaparib -8
diarrhoea -8 Treatment period
Treatment period -10
-10 6 months 12 months 18 months 24 months
12 months 6 months
18 months 24 months
Months from randomization
Months from randomization
*EORTC N&V score interpretation: ranges from 0-100; a higher score means more nausea/vomiting; positive change scores indicates more symptoms; Pre-specified clinically-meaningful difference is considered small if the change is
5-10 points and moderate if 10-20 points. †EORTC QLQ-C30 Diarrhoea score interpretation: ranges from 0-100; a higher score means more symptoms; positive change scores indicates more symptoms; Pre-specified clinically-
meaningful difference is considered small if the change is 5-10 points. ‡P-value <0.05. §Difference in the score between olaparib and placebo was 5-10.

Ganz PA, et al. Presented at SABCS 2021. 7–10 December. San Antonio, TX.
There were no clinically meaningful differences between olaparib and placebo
for Physical or Emotional Functioning subscale over time
EORTC QLQ-C30 Physical Functioning*
100 Neoadjuvant 100 Adjuvant
90 90

Physical Functioning scale score

Physical Functioning scale score

80 80
Better QoL

70 70
60 60
50 50
40 40
30 30
Placebo Placebo
20 20
Olaparib Olaparib
10 10
Treatment period Treatment period
0 0
6 months 12 months 18 months 24 months 6 months 12 months 18 months 24 months
Months from randomization Months from randomization

EORTC QLQ-C30 Emotional Functioning†

Adjuvant
100 Neoadjuvant 100
90 90

Physical Functioning scale score

Physical Functioning scale score

80 80
Better QoL

70 70
60 60
50 50
40 40
30 30
Placebo Placebo
20 20
Olaparib Olaparib
10 10
Treatment period Treatment period
0 0
6 months
18 months 12 months
24 months 6 months 12 months 18 months 24 months
Months from randomization Months from randomization
*EORTC QLQ-C30 Physical Functioning score interpretation: ranges from 0-100; a higher score means more QoL/functioning; Pre-specified clinically-meaningful difference is considered small if the change is 5-10 points and
moderate if 10-20 points. †EORTC QLQ-C30 Emotional Functioning score interpretation: ranges from 0-100; a higher score means more QoL/functioning; Pre-specified clinically-meaningful difference is considered small if the
change is 5-10 points and moderate if 10-20 points.
“No copiar y/o difundir de forma integral"
Ganz PA, et al. Presented at SABCS 2021. 7–10 December. San Antonio, TX.
 PARIB
OLA

m
BRCA

MATPROM: CO-11270 Prep: 08- 2023. AstraZeneca Colombia SAS, Edifício NAOS Avenida Carrera 9 No. 101-67 Oficina 601, tel.: (571) 3257200. En caso de evento adverso repórtelo en Colombia a la línea 01800011156 a
patientsafetycolombia@astrazeneca.com o ingrese a https://aereporting.astrazeneca.com y seleccione en país Colombia. Material dirigido al cuerpo médico. La información incluida en esta presentación puede hacer referencia a medicamentos o indicaciones
que podrían no estar aprobadas en el país. Se presentan exclusivamente con fines educativos, considerando el derecho de la comunidad médica a estar debidamente informada en relación con los avances científicos más recientes, según lo establece el código
de la IFPMA. Bajo ninguna circunstancia esta información debe ser considerada como una recomendación para el uso de medicamentos o indicaciones. Por favor, consulte la IPP local"
 Inmunoterapia KN 522 : PEMBROLIZUMAB
Randomized, placebo-controlled phase III trial

Primary endpoints: pCR (ypT0/Tis ypN0) by local review, EFS by local review

Secondary endpoints: pCR (ypT0 ypN0 and ypT0/Tis), OS, EFS (PD-L1+), safety, QoL

https://clinicaloptions.com/
Inmunoterapia KN 522 : PEMBROLIZUMAB
Respuesta patológica completa

Schmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J, Denkert C, Park YH, Hui R, Harbeck N, Takahashi M, Foukakis T, Fasching PA, Cardoso F, Untch M, Jia L, Karantza V, Zhao J, Aktan G,
Dent R, O'Shaughnessy J; KEYNOTE-522 Investigators. Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med. 2020 Feb 27;382(9):810-821. doi: 10.1056/NEJMoa1910549. PMID:
32101663.
Inmunoterapia KN 522 : PEMBROLIZUMAB
Sobrevida libre de eventos
Inmunoterapia KN 522 : PEMBROLIZUMAB
Sobrevida libre de eventos

Schmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J, Denkert C, Park YH, Hui R, Harbeck N, Takahashi M, Foukakis T, Fasching PA, Cardoso F, Untch M, Jia L, Karantza V, Zhao J, Aktan G,
Dent R, O'Shaughnessy J; KEYNOTE-522 Investigators. Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med. 2020 Feb 27;382(9):810-821. doi: 10.1056/NEJMoa1910549. PMID:
32101663.
 Inmunoterapia - NA - KN522
Eventos adversos inmunomediados:
● Grado ≽ 3: 81 vs 76%
● EA discontinuación 23 vs 12%

Schmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J, Denkert C, Park YH, Hui R, Harbeck N, Takahashi M, Foukakis T, Fasching PA, Cardoso F, Untch M, Jia L, Karantza V, Zhao J, Aktan G,
Dent R, O'Shaughnessy J; KEYNOTE-522 Investigators. Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med. 2020 Feb 27;382(9):810-821. doi: 10.1056/NEJMoa1910549. PMID:
32101663.
 Inmunoterapia - KN522

Schmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J, Denkert C, Park YH, Hui R, Harbeck N, Takahashi M, Foukakis T, Fasching PA, Cardoso F, Untch M, Jia L, Karantza V, Zhao J, Aktan G,
Dent R, O'Shaughnessy J; KEYNOTE-522 Investigators. Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med. 2020 Feb 27;382(9):810-821. doi: 10.1056/NEJMoa1910549. PMID:
32101663.
Abemaciclib
San Antonio Breast Cancer Symposium ®, December 6-10, 2022

monarchE Study Design (NCT03155997)

Cohort 1: High risk based On-study treatment period

HR+, HER2-, node on clinical pathological 2 years
positive high-risk features
EBC • ≥4 ALN OR
• 1-3 ALN and at least 1 of the
Abemaciclib
• Women or men below: (150mg twice daily)
• Pre-/postmenopausal • Grade 3 disease +
Follow-up period
• With or without prior • Tumor size ≥5 cm Endocrine Therapy: AI or tamoxifen
R 1:1 Endocrine Therapy
neo- and/or adjuvant
N = 5637 3-8 years as clinically
chemotherapy
indicated
• No metastatic disease Cohort 2: High risk based
• Maximum of 16 Endocrine Therapy: AI or tamoxifen
on Ki-67
months from surgery to • 1-3 ALN and
randomization and 12 • Ki-67 ≥20% and
weeks of ET following • Grade 1-2 and tumor size <5 Primary Objective: IDFS
the last non-ET cm Secondary Objectives: IDFS in high Ki-67 populations, DRFS, OS, Safety, PK, PRO

ITT Population
Stratified for: Cohort 1
• Prior chemotherapy
Cohort 2
• Menopausal status 91%
• Region
9%
This presentation is the intellectual property of the author/presenter. Contact them at stephen.johnston@rmh.nhs.uk for permission to reprint and/or distribute.
 San Antonio Breast Cancer Symposium ®, December 6-10, 2022

IDFS Benefit in ITT Persists Beyond Completion of Abemaciclib

Number of IDFS events

Abemaciclib + ET ET Alone
336 499
HR (95% CI): 0.664 (0.578, 0.762)
Nominal p < 0.0001

33.6% reduction in the risk of developing an IDFS event with an increase in absolute
benefit in IDFS 4-year rates (6.4%) compared to 2-and 3-year IDFS rates (2.8% and 4.8% respectively)
This presentation is the intellectual property of the author/presenter. Contact them at stephen.johnston@rmh.nhs.uk for permission to reprint and/or distribute.
Abemaciclib
San Antonio Breast Cancer Symposium ®, December 6-10, 2022

DRFS Benefit in ITT Persists Beyond Completion of Abemaciclib

Number of DRFS events

Abemaciclib + ET ET Alone
281 421
HR (95% CI): 0.659 (0.567, 0.767)
Nominal p < 0.0001

34.1% reduction in the risk of developing a DRFS event with an increase in absolute
benefit in DRFS 4-year rates (5.9%), compared to 2-and 3-year rates (2.5% and 4.1%, respectively)
This presentation is the intellectual property of the author/presenter. Contact them at stephen.johnston@rmh.nhs.uk for permission to reprint and/or distribute.
Abemaciclib
San Antonio Breast Cancer Symposium ®, December 6-10, 2022

OS Data Remain Immature in ITT

Number of OS events
Abemaciclib + ET ET Alone
157 173
HR (95% CI): 0.929 (0.748, 1.153)
Log-rank P = 0.5027

Fewer deaths (157 vs 173) were observed in the abemaciclib plus ET group versus the ET group
This presentation is the intellectual property of the author/presenter. Contact them at stephen.johnston@rmh.nhs.uk for permission to reprint and/or distribute.
Abemaciclib
San Antonio Breast Cancer Symposium ®, December 6-10, 2022

Fewer Patients with Metastatic Disease in the Abemaciclib arm

This presentation is the intellectual property of the author/presenter. Contact them at stephen.johnston@rmh.nhs.uk for permission to reprint and/or distribute.
Abemaciclib
San Antonio Breast Cancer Symposium ®, December 6-10, 2022

Safety Findings Consistent with Previous Analyses

Median duration of abemaciclib: 23.7 months.

Other events of Abemaciclib + ET ET Alone
interest, any grade N = 2791, % N = 2800, %
VTE 2.5 0.7
PE 1.0 0.1
ILD 3.3 1.3
Abemaciclib dose adjustments due to AEs
§ dose holds: 61.7%
§ dose reductions: 43.6%
§ discontinuations 18.5% [8.9% after dose reduction]

All patients who received at least one dose of study treatment were included in the safety population

The safety profile of abemaciclib is considered manageable and acceptable for this high-risk population
This presentation is the intellectual property of the author/presenter. Contact them at stephen.johnston@rmh.nhs.uk for permission to reprint and/or distribute.
Capecitabine
iPARP Vs Capecitabine

ORR de iPARP Vs Capecitabine:

• EMBRACA 63% Vs 27%
• OLYMPIAD 60% Vs 29% ( NO distingue QT , pero 45% era Cape)
iPARP Vs Pembrolizumab
• NO beneficio en OS ( hasta el momento) para pembro

• Impacto del pembrolizumab postoperatorio en estudio ( SWOG 1418,

NCT02954874)

• Sin signos de seguridad en múltiples estudios de combinación

ongoing.
iPARP Vs Pembrolizumab
iPARP Vs Abemaciclib
• Pacientes RH+ solo el 18% pero el beneficio es independiente del
estatus de RH
• Sin beneficio en SG con Abemaciclib ( hasta el momento) y
seguimiento a corto plazo para tumores RH+
• Estudios moleculares marcan genotipo BRCAness en pacientes con ca
de mama RH+ BRCAm
• Combinaciones de iPARP + iCDK NO SON POSIBLES por
mielosupresion.
• Enrolamiento en MonarchE hasta 16 meses luego de la cirugía:
Secuencial ?
Ensayos ongoing
Conclusiones
• Olaparib luego del tratamiento local y de quimioterapia (neo)
adyuvante mejora IDFS, DDFS y OS
• Olaparib : terapia estándar de mantenimiento en pacientes con
cáncer de mama temprano BRCAm de alto riesgo
• Olaparib es la única de la nuevas estrategias con un claro
biomarcador de selección de pacientes
• Necesidad de evaluar y diseñar un testeo temprano BRCAg
• Quedan preguntas sin contestar: como se ajustaran las otras
estrategias : Pembro, Cape y Abema.
GRACIAS.