TY - JOUR
T1 - Combined PARP and HSP90 inhibition
T2 - preclinical and Phase 1 evaluation in patients with advanced solid tumours
AU - Konstantinopoulos, Panagiotis A.
AU - Cheng, Su Chun
AU - Supko, Jeffrey G.
AU - Polak, Madeline
AU - Wahner-Hendrickson, Andrea E.
AU - Ivy, S. Percy
AU - Bowes, Brittany
AU - Sawyer, Hannah
AU - Basada, Patrice
AU - Hayes, Martin
AU - Curtis, Jennifer
AU - Horowitz, Neil
AU - Wright, Alexi A.
AU - Campos, Susana M.
AU - Ivanova, Elena V.
AU - Paweletz, Cloud P.
AU - Palakurthi, Sangeetha
AU - Liu, Joyce F.
AU - D’Andrea, Alan D.
AU - Gokhale, Prafulla C.
AU - Chowdhury, Dipanjan
AU - Matulonis, Ursula A.
AU - Shapiro, Geoffrey I.
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/4/1
Y1 - 2022/4/1
N2 - Purpose: PARP inhibitor resistance may be overcome by combinatorial strategies with agents that disrupt homologous recombination repair (HRR). Multiple HRR pathway components are HSP90 clients, so that HSP90 inhibition leads to abrogation of HRR and sensitisation to PARP inhibition. We performed in vivo preclinical studies of the HSP90 inhibitor onalespib with olaparib and conducted a Phase 1 combination study. Patients and methods: Tolerability and efficacy studies were performed in patient-derived xenograft(PDX) models of ovarian cancer. Clinical safety, tolerability, steady-state pharmacokinetics and preliminary efficacy of olaparib and onalespib were evaluated using a standard 3 + 3 dose-escalation design. Results: Olaparib/onalespib exhibited anti-tumour activity against BRCA1-mutated PDX models with acquired PARPi resistance and PDX models with RB-pathway alterations(CDKN2A loss and CCNE1 overexpression). Phase 1 evaluation revealed that dose levels up to olaparib 300 mg/onalespib 40 mg and olaparib 200 mg/onalespib 80 mg were safe without dose-limiting toxicities. Coadministration of olaparib and onalespib did not appear to affect the steady-state pharmacokinetics of either agent. There were no objective responses, but disease stabilisation ≥24 weeks was observed in 7/22 (32%) evaluable patients including patients with BRCA-mutated ovarian cancers and acquired PARPi resistance and patients with tumours harbouring RB-pathway alterations. Conclusions: Combining onalespib and olaparib was feasible and demonstrated preliminary evidence of anti-tumour activity.
AB - Purpose: PARP inhibitor resistance may be overcome by combinatorial strategies with agents that disrupt homologous recombination repair (HRR). Multiple HRR pathway components are HSP90 clients, so that HSP90 inhibition leads to abrogation of HRR and sensitisation to PARP inhibition. We performed in vivo preclinical studies of the HSP90 inhibitor onalespib with olaparib and conducted a Phase 1 combination study. Patients and methods: Tolerability and efficacy studies were performed in patient-derived xenograft(PDX) models of ovarian cancer. Clinical safety, tolerability, steady-state pharmacokinetics and preliminary efficacy of olaparib and onalespib were evaluated using a standard 3 + 3 dose-escalation design. Results: Olaparib/onalespib exhibited anti-tumour activity against BRCA1-mutated PDX models with acquired PARPi resistance and PDX models with RB-pathway alterations(CDKN2A loss and CCNE1 overexpression). Phase 1 evaluation revealed that dose levels up to olaparib 300 mg/onalespib 40 mg and olaparib 200 mg/onalespib 80 mg were safe without dose-limiting toxicities. Coadministration of olaparib and onalespib did not appear to affect the steady-state pharmacokinetics of either agent. There were no objective responses, but disease stabilisation ≥24 weeks was observed in 7/22 (32%) evaluable patients including patients with BRCA-mutated ovarian cancers and acquired PARPi resistance and patients with tumours harbouring RB-pathway alterations. Conclusions: Combining onalespib and olaparib was feasible and demonstrated preliminary evidence of anti-tumour activity.
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U2 - 10.1038/s41416-021-01664-8
DO - 10.1038/s41416-021-01664-8
M3 - Article
C2 - 34887522
AN - SCOPUS:85120943852
SN - 0007-0920
VL - 126
SP - 1027
EP - 1036
JO - British journal of cancer
JF - British journal of cancer
IS - 7
ER -