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Updated: Oct 10, 2025
Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics
Published on: October 2, 2014
Combined PARP and HSP90 inhibition: preclinical and Phase 1 evaluation in patients with advanced solid tumours
Panagiotis A Konstantinopoulos1, Su-Chun Cheng2, Jeffrey G Supko3
1Dana-Farber Cancer Institute, Boston, MA, USA. panagiotis_konstantinopoulos@dfci.harvard.edu.
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.
Insights
Combining HSP90 inhibitor onalespib with olaparib shows promise for overcoming PARP inhibitor resistance in ovarian cancer. This combination demonstrated anti-tumor activity and disease stabilization in preclinical and early clinical studies.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- PARP inhibitor (PARPi) resistance is a significant challenge in ovarian cancer treatment.
- Homologous recombination repair (HRR) pathway defects are implicated in PARPi sensitivity.
- HSP90 inhibition can disrupt HRR, potentially sensitizing tumors to PARPi.
Purpose of the Study:
- To evaluate the preclinical efficacy of combining the HSP90 inhibitor onalespib with olaparib in ovarian cancer models.
- To assess the safety, tolerability, pharmacokinetics, and preliminary efficacy of the onalespib and olaparib combination in a Phase 1 clinical trial.
Main Methods:
- In vivo studies using patient-derived xenograft (PDX) models of ovarian cancer.
- A standard 3+3 dose-escalation Phase 1 clinical trial design.
- Evaluation of safety, tolerability, steady-state pharmacokinetics, and preliminary anti-tumor activity.
Main Results:
- The combination exhibited anti-tumor activity in BRCA1-mutated PDX models with acquired PARPi resistance and RB-pathway altered models.
- The combination was safe and well-tolerated up to specific dose levels, with no dose-limiting toxicities observed.
- Disease stabilization for ≥24 weeks was observed in 32% of evaluable patients, including those with BRCA-mutated or RB-pathway altered tumors.
Conclusions:
- Combining onalespib and olaparib is a feasible strategy for ovarian cancer treatment.
- The combination demonstrated preliminary evidence of anti-tumor activity, particularly in resistant or altered tumor types.
- Further investigation of this combination therapy is warranted.
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