Abstract
HOPE: Harnessing olaparib, palbociclib, and endocrine therapy for BRCA1/2-associated HR+, HER2- metastatic breast cancer.
Author
Payal Deepak Shah
Penn Medicine Abramson Cancer Center, Philadelphia, PA
info_outline
Payal Deepak Shah, Alexandra Torres, Megan Aaron, Vivek Narayan, Hayley Michelle Knollman, Angela R. Bradbury, Angela DeMichele, Mark E. Robson, Nadine M. Tung, Susan M. Domchek
Full text
Authors
Payal Deepak Shah
Penn Medicine Abramson Cancer Center, Philadelphia, PA
info_outline
Payal Deepak Shah, Alexandra Torres, Megan Aaron, Vivek Narayan, Hayley Michelle Knollman, Angela R. Bradbury, Angela DeMichele, Mark E. Robson, Nadine M. Tung, Susan M. Domchek
Organizations
Penn Medicine Abramson Cancer Center, Philadelphia, PA, University of Pennsylvania, Abramson Cancer Center, Philadelphia, PA, Hospital of the University of Pennsylvania, Philadelphia, PA, University of Pennsylvania, Philadelphia, PA, Memorial Sloan Kettering Cancer Center, New York, NY, Beth Israel Deaconess Medical Center, Boston, MA
Abstract Disclosures
Research Funding
No funding sources reported
Background:
Thepoly (ADP-ribose) polymerase inhibitor olaparib yields superior progression-free survival, response rates and patient-reported outcomes compared with chemotherapy in patients with
BRCA1
-
or
BRCA2
-
(
BRCA1/2
)
associated metastatic breast cancer (MBC). Fulvestrant and palbociclib improve outcomes in patients with hormone receptor-positive (HR+) MBC. HOPE (NCT03685331) is a phase I trial to evaluate combination olaparib (O), fulvestrant (F), and palbociclib (P) in patients with
BRCA1/2
-associated HR+, HER2 negative MBC.
Methods:
A 3+3 dose escalation was used to assess safety and preliminary efficacy of O, F and P. Eligible participants (pts) had HR+ MBC, a germline (g) or somatic (s) mutation in
BRCA1/2
, measurable/evaluable disease, any/no prior endocrine therapy, and 0-2 prior lines of chemotherapy for MBC. Prior PARPi and CDK4/6i were permitted but not in combination. Palbociclib was added after a 28-day safety run-in (Cycle 0) of O + F alone. Fulvestrant dose was 500mg IM on day 1 of each 28-day cycle. Dose level 0 (DL0, starting level) was F, O 300mg orally BID continuously, P 75mg orally daily on days 1-21; DL-1 was F, O 250mg orally BID, P 75mg orally daily on days 1-21. The primary endpoint was MTD (adverse events (AEs) based on CTCAE v5.0). Dose limiting toxicity (DLT) period included Cycles 0 and 1. A 30% DLT rate was acceptable; 6 pts had to be treated at a dose for it to be declared MTD. RECIST v1.1 was used to evaluate response.
Results:
Eight treated pts (s
BRCA1:
1
;
g
BRCA2:
6; s
BRCA2:
1
)
had median (M) age 47; M 0 (0-2) prior lines of endocrine therapy and 0 (0-1) prior chemotherapies for MBC. Three pts each had received O, F, and CDK4/6i as part of their standard of care treatment before study. At DL0, 2/2 pts had DLT with persistent grade(G) 3 neutropenia. Among 6 pts treated at DL-1, none experienced DLT, but 3 pts missed doses of study treatment due to cytopenias (G3 neutropenia, G3 leukopenia, G3 thrombocytopenia) during the DLT period. Following the DLT period, 1 pt reduced O to 200mg orally daily and 1 discontinued P based on provider discretion due to cytopenias (G3 neutropenia, G3 thrombocytopenia). Grade 3 AEs occurring in >1 pt related to study treatment were: neutrophil count decrease (G3/2, n=5/2); white blood cell decrease (G3/2/1, n=3/2/2); platelet count decrease (G3/2/1, n=2/0/1). Overall related AEs in >50% of pts were anemia (n=7), fatigue (n=6) and nausea (n=5). Best responses were CR/PR/SD/PD in 1/1/5/1 pts.
Conclusions:
MTDof O, F and P (DL-1) was reached and demonstrated antitumor activity. Although no AEs meeting protocol-specified DLT criteria were observed at MTD, hematologic toxicity at this dose complicated drug delivery and required close monitoring during and after the DLT period. Combinations utilizing PARP1 selective inhibitors, lower doses of therapy or sequential rather than combination therapy may improve feasibility. Clinical trial information: NCT03685331.
6 organizations
3 drugs
6 targets
Drug
olaparibDrug
fulvestrantDrug
palbociclibTarget
Estrogen Receptor (ER)Target
BRCA2Target
CDK6Target
CDK4 & 6Target
PARP1Target
BRCA1Organization
Penn Medicine Abramson Cancer CenterOrganization
University of PennsylvaniaOrganization
Abramson Cancer CenterOrganization
Hospital of the University of PennsylvaniaOrganization
Memorial Sloan Kettering Cancer CenterOrganization
Beth Israel Deaconess Medical Center