Endocrine Therapy
for Advanced Breast
Cancer (ABC)
Dr Yoon-Sim YAP
Division of Medical Oncology,
National Cancer Centre Singapore
2
Outline
• Guidelines and Evolving Clinical Treatment Landscape
for HR+ HER2- advanced breast cancer (ABC)
• Optimising endocrine therapy backbone
• Improving outcomes further with targeted therapy
• Sequencing of Treatments
– First Line setting vs Second-line setting & beyond
– Predictive Biomarkers
• Other Novel Therapeutic Strategies
• Conclusions
Treatment guidelines for HR+, HER2– advanced breast cancer
ESMO1 In HR+, HER2– disease, endocrine therapy is the treatment of first
choice independent of metastatic site, unless rapid response is
needed. Limited visceral metastases are not a contraindication for
endocrine therapy
ABC2 Endocrine therapy is the preferred option for HR+ disease, even in
the presence of visceral disease, unless there is concern or proof
of endocrine resistance or rapidly progressive disease needing a
fast response
ASCO3 Endocrine therapy should be recommended as initial treatment for patients with HR+ metastatic breast cancer except in patients with immediately life-threatening disease or in those with rapid visceral recurrence on adjuvant endocrine therapy.
NCCN4 Endocrine therapy recommended unless there is visceral crisis, or
progression with no clinical benefit after 3 sequential endocrine therapy regimens.
3
1. Cardoso F et al. Ann Oncol 2012;23(Suppl 7):vii11-vii19 2. Cardoso F et al. Ann Oncol
2014;25(10):1871–1888 3. ASCO 2016. Available at https://www.asco.org/sites/new-
www.asco.org/files/content-files/practice-and-guidelines/documents/2016-adv-endocrine-breast-summary-
table.pdf 4. NCCN V3.2017. Available at https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf
4
Chemotherapy versus Endocrine Therapy
Wilcken et al, Cochrane System Database Review 2009
Chemotherapy has higher response rate.
5
Chemotherapy versus Endocrine Therapy
Wilcken et al, Cochrane System Database Review 2009
No significant differences in overall survival.
What are the Endocrine Therapy
Options?
What is the evidence for doing what
we do? (ie if people are practising
evidence-based medicine)
6
7
Breakthroughs in hormone receptor positive (HR+) breast cancer
1977Tamoxifen
1996Goserelin
1999Exemestane
2002Fulvestrant
2015Palbociclib + Letrozole
2016Palbociclib +Fulvestrant
1997Letrozole
FDA approvals of new treatments
2012Everolimus
+ Exemestane
Co
mb
inati
on
Th
era
py
19951980 2000 20162015
En
do
cri
ne
Th
era
py
2017Ribociclib(with AI)
2017
2017Abemaciclib(single agent
or with fulvestrant)
1995Anastrozole
1985MegestrolAcetate
8
ASCO Guidelines
Rugo et al, JCO 2016
Postmenopausal
Premenopausal
Courtesy of Ian Smith from ESMO 2014
Mechanism of Action of Tamoxifen
and Aromatase Inhibitors
Johnston, Nature Reviews Cancer 2003
First-line Comparative Tamoxifen Trials in
Advanced Breast Cancer 1981-96 (2004)
12
Tamoxifen versus
N=17
Progestogens 6Estrogens 1Androgens 1Anti-Estrogens 2Aminogluthetimide 3Formestane 1Fadrozole 2Fulvestrant 1
Tamoxifen always better or at least as good.
Schiavon and Smith, Haematol Oncol Clin North AM 2013
Rationale for OS + Tamoxifen in
Premenopausal MBC
Randomised study: n=161 (original target 348)
Combined treatment with buserelin and tamoxifen was superior to treatment with buserelin or tamoxifen alone by
• objective response rate (48%, 34%, and 28% of patients who could be evaluated,respectively; P = .11 [x2 test]),
• median progression-free survival (9.7 months, 6.3 months, and 5.6 months; P = .03), and
• overall survival (3.7 years, 2.5 years, and 2.9 years; P = .01).
• 5-year survival were 34.2% (95% confidence interval [CI] = 20.4%–48.0%), 14.9% (95% CI =3.9%–25.9%), and 18.4% (95% CI = 7.0%–29.8%), respectively.
13
Klijn et al, JNCI 2000
Use of 2nd line AIs v megesterol acetate
AIs: RR, TTP and overall survival only slightly better than megestrol acetate
Smith NEJM 2003
Progestins
• Mechanism of action unclear.
• May inhibit aromatase activity or increase estrogen turnover, since estrogen levels fall during therapy.
• May also act through the glucocorticoid receptor, androgen receptor, or progesterone receptor.
• Activity appears to be maintained in patients who are refractory to SAIs.
• Side-effects: weight gain, fluid retention, thromboembolic complications, PV bleeding.
Willemse, EJC 1990; Abrams, JCO 1999
What is the optimal 1st-line endocrine therapy?
16
TrialAI
(response rate, %)
Tamoxifen (response
rate, %)
AI (PFS, mths)
Tamoxifen(PFS, mths)
Hazard Ratio
Nabholtz et al, 2000 (n=353)Anastrozole vs tamoxifen
21 17 11.1 5.6 0.81
Bonneterre et al, 2001 (n=668)Anastrozole vs tamoxifen
33 33 8.2 8.3 0.99
Mouridsen et al, 2001 (n=907)Letrozole vs tamoxifen
30 20 9.4 6.0 0.72
Paridaens et al, 2008 (n=371)Exemestane vs tamoxifen
46 31 9.9 5.8 0.84
Range 8–12 6–8
PFS / TTP of AIs as 1st-line endocrine therapy trials in HR+ MBC
Johnston, SABCS 2016
Meta-analysis: compared to tamoxifen, there was a statistically significant
survival benefit (11 percent relative hazard reduction, 95% CI 1 to 19 percent)
for first-line third generation SAIs, but not for aminoglutethimide or second
generation SAIs. Mauri et al, JNCI 2006
AI + Ovarian Suppression in Premenopausal
• Is it better than tamoxifen + ovarian suppression??
• No randomised trials with tamoxifen and OS for comparison in metastatic setting.
17
What are the endocrine options after AI?
• How good is tamoxifen after an AI?
– TAMRAD (Tamoxifen vs Tamoxifen + Everolimus after AI) (Bachelotet al, JCO 2012) Tamoxifen arm (26% received 1 line of palliative chemo): 6mth clinical benefit rate 42%; TTP 4.5 mths; response rate 13%
• How good is exemestane (monotx) after an AI?
– EFECT (Chia, JCO 2008): median TTP 3.7mths; response rate 6.7%
– SOFEA (Johnston, Lancet Oncol 2013): median PFS 3.4mths; response rate 2.8%
– BOLERO-2 (Baselga, NEJM 2012): median PFS 2.8mths, response rate 0.4%.
• How good are progestins after an AI?
– No prospective data
• How good is fulvestrant after an AI?
– See following ….
18
No
dimerisation
NO
TRANSCRIPTION
(no tumour cell
division)
AF1 + AF2
INACTIVE
Fulvestrant
AF1
ER+F F F
ACCELERATED RECEPTOR DEGRADATION
Adapted from: Wakeling AE. Endocr-Relat Cancer 2000; 7: 17–28.
Mode of Action of Estradiol, Tamoxifen
and Fulvestrant
Tamoxifen
AF1
ER+
PARTIALLY
INACTIVATED
TRANSCRIPTION
(reduced rate of
tumour cell
division)
T T
T
AF1
AF1
ACTIVE
AF2
INACTIVE
AF1
ERE
E
E+ AF1 +
AF2
ACTIVEReceptor
dimerisation
FULLY
ACTIVATED
TRANSCRIPTION
(tumour cell
division)
AF2
AF1
Estradiol
20
Fulvestrant: Preclinical Activity
Osborne et al, JNCI 1995 Osborne et al, Cancer
Chemo and Pharm 1994
21
Clinical Trials on Fulvestrant (250mg LD)
Howell, JCO 2004
Howell, JCO 2002 Osborne, JCO 2002
Only just as good as
tamoxifen or anastrozoleTreatment-naive
Pretreated Pretreated
22
Clinical Trials on Fulvestrant (250mg LD)
Only just as good as exemestane
even after relapse/progresson on
non-steroidal AI
Caveat: 250mg dose was
suboptimal
Johnston, Lancet Oncol 2013
Chia, JCO 2008
CONFIRM phase III Trial:
Fulvestrant 250mg vs 500mg
Di Leo et al, JNCI 2014
Median OS 26.4mths vs 22.3mths
24
Clinical Trials on Fulvestrant (500mg HD)
Ellis et al, JCO 2015
Caveat: OS not preplanned analysis; not all patients participated in OS followup.
Primary Endpoint:
CBR fulvestrant HD
vs anastrozole
72.5% v 67.0%
(odds ratio, 1.30;
95% CI, 0.72 to
2.38; P .386).
Robertson et al, JCO 2009
▪ ER +ve , HER2 negative
▪ Locally advanced (not suitable for
surgery) or metastatic disease
▪ Up to 1 line of chemotherapy
▪ At least 1 lesion that can be assessed
FALCON: Phase III 1st line study of
Fulvestrant 500 vs AI in Endocrine
Therapy Naïve MBC / LABC
• Primary endpoint: PFS
• Secondary endpoint: OS
– Other secondary endpoints include ORR, CBR, duration of response, duration of clinical
benefit, time to deterioration of HRQoL, Safety
Fulvestrant 500mg i.m.
Anastrozole1mg OD
N=450
Note no prior endocrine therapy allowed
Ellis et al, LBA14 ESMO 2016
FALCON: Fulvestrant 500 vs anastrozole in
1st-line endocrine therapy naïve ER+ MBC
HR 0.797
(95% CI 0.637, 0.999)
p=0.0486
Median PFS
Fulvestrant: 16.6 months
Anastrozole: 13.8 months
Number of
patients at risk:
Fulvestrant
Anastrozole
230
232
187
194
171
162
150
139
124
120
110
102
96
84
81
60
63
45
44
31
24
22
11
10
2
0
0
0
Pro
po
rtio
n o
f p
ati
en
ts a
live
an
d p
rog
res
sio
n f
ree
Time (months)
0.9
1.0
0.7
0.8
0.5
0.6
0.3
0.4
0.1
0.00 3 6 9 12 15 18 21 24 27 30 3633 39
0.2
Fulvestrant (n=230)
Anastrozole (n=232)
PFS without visceral disease
HR 0.59
(95% CI 0.42, 0.84)
Median PFS
Fulvestrant: 22.3 months
Anastrozole: 13.8 monthsPro
po
rtio
n o
f p
ati
en
ts a
live
an
d p
rog
res
sio
n-f
ree
Time (months)
0.9
1.0
0.7
0.8
0.5
0.6
0.3
0.4
0.1
0.0
0.2
0 5 10 15 20 25 30 35 40
Fulvestrant (n=95) Anastrozole (n=113)
PFS with visceral disease
Pro
po
rtio
n o
f p
ati
en
ts a
live
an
d
pro
gre
ssio
n-f
ree
Time (months)
0.9
1.0
0.7
0.8
0.5
0.6
0.3
0.4
0.1
0.0
0 5 10 15 20 25 30 35 40
0.2
HR 0.99
(95% CI 0.74, 1.33)
Median PFS
Fulvestrant: 13.8 months
Anastrozole: 15.9 months
Fulvestrant (n=135)
Anastrozole (n=119)
Primary endpoint: PFS
Ellis et al, LBA14 ESMO 2016; Robertson et al, Lancet 2016
What is the optimal 1st-line endocrine therapy?
27
Trial DateAI
(months)Tamoxifen(months)
AI + fulvestrant 250mg (months)
Fulvestrant500mg
(months)
Hazard Ratio
Nabholtz et alAnastrozole vs tamoxifen
2000 11.1 5.6 - 0.81
Bonneterre et al Anastrozole vs tamoxifen
2001 8.2 8.3 - 0.99
Mouridsen et al Letrozole vs tamoxifen
2001 9.4 6.0 - 0.72
Chernozemsky et alExemestane vs tamoxifen
2007 12.0 8.3 - -
Paridaens et alExemestane vs tamoxifen
2008 9.9 5.8 - 0.84
Mehta et alAnastrozole vs anastrozole + fulvestrant 250mg
2012 13.5 - 15.0 0.80
Bergh et alAnastrozole vs anastrozole + fulvestrant 250mg
2012 10.2 - 10.8 0.99
Ellis et alAnastrozole vs Fulvestrant500mg
2016 13.8 16.6 0.797
Range 8–13 6–8 10–15 16-17
PFS / TTP of AIs as 1st-line endocrine therapy trials in HR+ MBC
Is Fulvestrant the gold standard for 1st-line treatment now?
• PFS benefit “modest”
• PFS benefit restricted to patients without visceral mets.
• Only applies to endocrine naïve patients?
• Activity of other endocrine therapies post-fulvestrant unclear.
• Await overall survival data …. …….
• Other more effective alternative options available now.
28
ESR1 Mutations
Toy et al, Nature Genetics 2013
New generation SERDs (Selective
Estrogen Receptor Degraders - oral)
• Limitations of fulvestrant
– Poor bioavailability
– Requires oil-based IM formulation; limitations with increasing dose intensity
– Variable ER down-regulation
29
Van Kruchten et al, 2015
SERD Company Current status
GDC-0810 Genentech Phase I/II
GDC-0927 Genentech Phase I
RAD1901 Radius Phase I
AZD9496 Astra Zeneca Phase I
LSZ-102 Novartis Phase I
SAR439859 Sanofi Phase I
H3b-6545 (SERCA) H3 BioMedicine Phase I
FDA
Breakthrough
Drug
Designation
2017
Definitions of Endocrine Resistance in ER+ MBC
PRIMARY ENDOCRINE RESISTANCE
Relapse while on the first 2 years of
adjuvant ET, or PD within first 6 months
of 1st line ET for MBC, while on ET
SECONDARY (ACQUIRED) ENDOCRINE RESISTANCE
Relapse while on adjuvant ET but after the first 2 years,
or relapse within 12 months of completing adjuvant ET,
or PD ≥ 6 months after initiating ET for MBC, while on ET
Courtesy of Johnston, SABCS 2016; Cardoso, Annals Onc 2014
What can we add to endocrine therapy to
overcome endocrine resistance?
31
• First-line setting
– CDK4/6 Inhibitor
(Trials using Temsirolimus, Bevacizumab, EGFR Inhibitors negative
or mixed results.)
• Second-line and beyond
– CDK4/6 Inhibitor vs mTOR Inhibitor
– ? PI3K inhibitor
Cyclin Dependent Kinase(CDK) 4/6 Inhibitors
32
Lange and Yee, Endocrine Related Cancer 2011
Ma, ASCO 2016
CDK4/6 Inhibitors
O’Leary et al, Nat Rev Clin Onc 2016
PALOMA-2 & MONALEESA-2: Design of Phase III
Studies
• Primary endpoint: PFS
• Secondary endpoints:
– Response, OS, safety, biomarkers, PROs
PALOMA-2
R
A
N
D
O
M
I
S
E
Palbociclib (125 mg QD, 3/1
schedule) + letrozole
(2.5 mg QD)
Placebo + letrozole
(2.5 mg QD)
Postmenopausal ER+
HER2– advanced
breast cancer with no
prior treatment for
advanced disease.
AI-resistant patients
excluded
N=666
(2:1)
Stratified by the presence/absence of
liver and/or lung metastases
Ribociclib (600 mg QD,
3/1 schedule) +letrozole
(2.5 mg QD)
Placebo+ letrozole
(2.5 mg QD)
• Primary endpoint: PFS
• Secondary endpoints:
– OS (key), ORR, CBR, safety
Postmenopausal
women with
HR+/HER2–
advanced breast
cancer with
no prior therapy for
advanced disease
N=668
MONALEESA-2
R
A
N
D
O
M
I
S
E
(1:1)
Courtesy of Johnston, SABCS 2016
PALOMA-2
Finn R, et al. NEJM. 2016;375(20):1925–1936
mPFS (months)Palbociclib–letrozole: 24.8Placebo–letrozole: 14.5
MONALEESA-2
Hortobagyi G, et al. NEJM. 2016;375(18):1738–1748
mPFS (months)ribociclib–letrozole: NRplacebo–letrozole: 14.7
PALOMA-2 & MONALEESA-2: PFS
mPFS (months)Ribociclib–letrozole: NRPlacebo–letrozole: 14.7
PALOMA-2 & MONALEESA-2: Secondary
endpoints
PALOMA-2Measurable disease
MONALEESA-2Measurable disease
55.3
84.3
44.4
70.8
0
10
20
30
40
50
60
70
80
90
100
Objective response rate Clinical benefit rate
Palbociclib + letrozole
Placebo + letrozole
53
80.1
37
71.8
0
10
20
30
40
50
60
70
80
90
100
Objective response rate Clinical benefit rate
Ribociclib + letrozole
Placebo + letrozole
OR (95% CI): 1.55 (1.05–2.28)p=0.03
OR (95% CI): 2.23 (1.39–3.56)p<0.001
p=0.00028
p=0.02
Rat
e (%
)
Finn R, et al. NEJM. 2016;375(20):1925–1936
Finn R, et al. Abstract 507, ASCO 2016
Hortobagyi G, et al. NEJM. 2016;375(18):1738–1748
Hortobagyi G, et al. LBA01, ESMO 2016
Rat
e (%
)
PALOMA-2 MONALEESA-2
Finn R, et al. NEJM. 2016;375(20):1925–1936 Hortobagyi G, et al. NEJM. 2016;375(18):1738–1748
PALOMA-2 & MONALEESA-2: Toxicity
Other potential AEs: Transaminitis, prolonged QT
MONARCH-1: Abemaciclib (Inhibitor of
CDK4>CDK6)
38
Dickler et al, ASCO 2016; CCR 2017
• Phase 2 single-agent trial in metastatic HR+HER2- mBC.
• No. of prior systemic regimens (any setting); 5 (2-11).
• 1-2 chemotherapy regimens in metastatic setting.
MONARCH-3
39
Goetz et al, JCO 2017
MONARCH-3
40
Goetz et al, JCO 2017
CDK 4/6 inhibitors for ER+ MBC
• New “Gold Standard” in 1st-line treatment
• Adjuvant trials have also commenced.
Unanswered Questions
• Does every patient need CDK4/6 inhibitor upfront?
Potential Predictors of CDK4/6 Inhibitor Activity
In sensitive cell lines:
• ↑ Cyclin D1 (CCND1)
• ↑ Retinoblastoma (Rb)
• ↓ p16
Finn RS, et al. Br Ca Research 2009 Finn RS, et al. Lancet Oncol 2015
ER+HER2- Unselected
ER+HER2- Plus
Amplification of CCND1
and/or Loss of p16
PALOMA-1
Predictive Biomarkers?
PALOMA-2: No subgroup of ER+ patients was found that
did not benefit from the addition of palbociclib to letrozole.
43
Finn RS, et al. ESMO 2016. Abstract LBA15 [oral].
Predictive Biomarkers?Ribociclib + letrozole for first-line treatment of hormone receptor-positive (HR+), HER2-
negative (HER2–) advanced breast cancer (ABC): efficacy by baseline tumor markers
44
Andre et al, AACR 2017
Subgroup Analyses
45
Hortobagyi et al, NEJM 2016Finn et al, NEJM 2016
PALOMA-2
MONALEESA-2
MONARCH-3
46
Goetz et al, JCO 2017
Patients with bone-only disease Patients without bone-only disease
Not all patients reach the next line of
ABC therapy
• After failure of first-line therapy, a proportion of patients cannot undergo second line therapy due to rapid disease progression
• In general, response to further lines of therapy is worse
• About one third of patients stop their treatment with each new line of therapy
• These results are concordant with large retrospective cohort studies
47
1. Dufresne A et al. Breast Cancer Res Treat 2008;107:275–279 2. Tacca O et al. Cancer Invest 2009;27:81–85
3. Bernardo G et al. Cancer Res 2010;70(Suppl 24):446s,P6-11-03 4. Planchat E et al. Breast 2011;20:574–578
5. Jackisch C et al. BMC Cancer 2014;14:924 6. Jackisch et al. P4-13-28, SABCS 2016
Study 2nd line 3rd line 4th line 5th line
Dufresne et al. 20081 100% 56% 25% 11%
Tacca et al. 20092 100% 68% 43% 23%
Bernardo et al. 20103 100% 82% 36% 11%
Planchat et al. 20114 100% 76% 56% 37%
Current study; Jackisch etal. 20145,6 100% 70% 46% 27%
Courtesy of Harbeck, ESMO Asia 2016
Considerations in choosing 1st-line therapy in ER+ MBC
Tumour Biology
• ER & PR levels
• Luminal Subtype / Proliferation
Clinical Features
• Prior Endocrine Rx / DFI / Pace of Disease
• Visceral vs non-visceral mets / Symptoms / Tumor Burden
Patient Factors
• Age / Co-morbidities / Geographical Logistics
• Patient Preference / Availability of Rx / Quality of Life
Partly adapted from Johnston, SABCS 2016
CDK 4/6 inhibitors for ER+ MBC
• New “Gold Standard” in 1st-line treatment
• Adjuvant trials have also commenced.
Unanswered Questions
• Does every patient need CDK4/6 inhibitor upfront?
• Will there be improvement in Overall Survival?
PALOMA-1 OS data (not powered)
50
Finn et al, ASCO 2017
MONALEESA-2 Update
(OS data still immature)
51
Hortobagyi et al, ASCO 2017
CDK 4/6 inhibitors for ER+ MBC
• New “Gold Standard” in 1st-line treatment.
• Adjuvant trials have also commenced.
Unanswered Questions
• Does every patient need CDK4/6 inhibitor upfront?
• Will there be improvement in Overall Survival?
• What is the optimal treatment after CDK4/6 Inhibition?
• What is the optimal sequence of treatment?
Second-Line and Beyond
BOLERO-2 & PALOMA-3: Design of Phase III studies
(2:1)
Palbociclib (125 mg
QD; 3 weeks on, 1
week off) +
fulvestrant (500 mg
IM Q4W)
(n=347)
Placebo
(3 weeks on, 1 week
off) + fulvestrant
(500 mg IM Q4W)
(n=174)
HR+, HER2- ABC
Pre/peri or postmenopausal
Progressed on prior ET on
or within 12 months of
adjuvant therapy and/or on
therapy for advanced breast
cancer
1 or more prior
chemotherapy regimen for
advanced cancer
• Primary endpoint: PFS
• Secondary endpoints:
– OS, ORR, Safety, QoL, CBR
(2:1)
Everolimus 10 mg daily +
exemestane 25 mg daily(n=485)
Placebo + exemestane 25 mg daily
(n=239)
Postmenopausal
women with estrogen
receptor positive
locally advanced or
metastatic breast
cancer who are
refractory to letrozole
or anastrozole
• Primary endpoint: PFS
• Secondary endpoints:
– OS, OR, CBR, Safety, QoL
BOLERO-2 PALOMA-3
R
A
N
D
O
M
I
S
E
R
A
N
D
O
M
I
S
E
BOLERO-2 & PALOMA-3: PFS
Turner N, et al. N Engl J Med 2015;373:209-19Baselga J, et al. N Engl J Med 2012;366:520-9
BOLERO-2 PALOMA-3
MONARCH-2
55
Sledge et al, ASCO 2017; JCO 2017
Patients were required to have disease that progressed while receiving neoadjuvant or adjuvant ET, # 12 months after adjuvant ET, or while receiving ET for ABC. Patients must not have received more than one ET or any prior chemotherapy for ABC.
BOLERO-2: Overall Survival Results
56
Piccart et al, Ann Onc 2014
Why?Not statistically powered to detect 4.4mth OS benefit.Imbalance in poststudy salvage chemo use?Higher rate of discontinuation of EVE due to AE: 26% vs 5%Paradoxical activation of AKT via negative feedback loop?Need predictive biomarkers?
BOLERO-2 Correlative Genomic Analysis
• Progression-free survival benefit with everolimus was maintained regardless of alteration status of PIK3CA, FGFR1, and CCND1 or the pathways of which they are components.
• However, mTOR somatic mutations may be associated with greater benefit from mTORinhibition.
• Somatic FGFR mutations associated with poor prognosis.
• High chromosomal instability associated with less everolimusbenefit and worst outcome.
57
Hortobagyi et al, JCO 2015
PI3K/AKT/mTOR Pathway
58
Rodon et al, Nature Reviews Clin Onc 2013
PI3K Inhibitors – still promising?
• Efficacy limited in unselected patients.
• Significant toxicities with Pan-PI3K Inhibitors.– FERGI (n=168): fulvestrant + pictilisib vs fulvestrant + placebo:
negative
– BELLE2 (n=1147): fulvestrant + buparlisib vs fulvestrant + placebo: positive but not clinically significant; benefit mainly with PIK3CA mutated (cDNA)
– BELLE3 (n=432)(post-mTOR inhibitor): fulvestrant + buparlisib vs fulvestrant + placebo: positive but not clinically significant; ; benefit mainly with PIK3CA mutated (tumour or cDNA)
• Alpha-specific PI3K Inhibitors– Better tolerated?
– Ongoing phase 3 trials• Taselisib + fulvestrant vs placebo + fulvestrant (SANDPIPER)
• Alpelisib + fulvestrant vs placebo + fulvestrant (SOLAR)
– Potential activity after progression on CDK4/6 Inhibitors?
59
Other Novel Therapeutics
• HDAC Inhibitors?
• Immunotherapy?
• Etc etc
• Still a role for
chemotherapy …
Ma et al, Nature Rev Ca 2015
Inhibitors of PI3K/MEK
pathway
Immunotherapy,
Bone-modifying agents
RTK Inhibitor
Novel SERD
Epigenetic Modulators?
Endocrine
Resistance
Inhibitors of MDM2?BCL2?
Inhibitors of NOTCH?WNT?CDK Inhibitor
61
Thank you for your attention!
Pink Ribbon Walk, October 2016