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Translational Therapeutics

Combined PARP and HSP90 inhibition: preclinical and Phase 1 evaluation in patients with advanced solid tumours

British Journal of Cancer volume 126, pages 1027–1036 (2022)Cite this article

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Abstract

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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Fig. 1: Olaparib and onalespib combination in ovarian PDX models.
Fig. 2: Response to study treatment (n = 22).
Fig. 3: Duration of treatment and time to progression (n = 22).

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Acknowledgements

We thank all the patients and their families for participation in the present trial.

Funding

The preclinical work was supported in part by the Department of Defense Ovarian Cancer Research Program Award DOD W81XWH-15-0564/OC140632 (PAK, Principal Investigator). The trial (clinicalTrials.gov Identifier: NCT02898207) was sponsored by the NCI-Cancer Therapy Evaluation Program (CTEP) and conducted under the auspices of the Experimental Therapeutics Clinical Trials Network (ETCTN). Dana-Farber/Harvard Cancer Center served as the lead site for the study, supported by NIH grant UM1 CA186709 (GIS, Principal Investigator). SPI is an employee of NIH and a member of NCI-CTEP as Associate Chief of the Investigational Drug Branch and Program Director of the ETCTN.

Author information

Author notes

  1. These authors contributed equally: Ursula A. Matulonis, Geoffrey I. Shapiro.

Authors and Affiliations

  1. Dana-Farber Cancer Institute, Boston, MA, USA

    Panagiotis A. Konstantinopoulos, Su-Chun Cheng, Madeline Polak, Brittany Bowes, Hannah Sawyer, Patrice Basada, Martin Hayes, Jennifer Curtis, Neil Horowitz, Alexi A. Wright, Susana M. Campos, Elena V. Ivanova, Cloud P. Paweletz, Sangeetha Palakurthi, Joyce F. Liu, Alan D. D’Andrea, Prafulla C. Gokhale, Dipanjan Chowdhury, Ursula A. Matulonis & Geoffrey I. Shapiro

  2. Massachusetts General Hospital, Boston, MA, USA

    Jeffrey G. Supko

  3. Mayo Clinic, Rochester, MN, USA

    Andrea E. Wahner-Hendrickson

  4. National Cancer Institute, Bethesda, MD, USA

    S. Percy Ivy

Authors
  1. Panagiotis A. Konstantinopoulos
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  2. Su-Chun Cheng
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  6. S. Percy Ivy
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  8. Hannah Sawyer
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  14. Susana M. Campos
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  15. Elena V. Ivanova
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  16. Cloud P. Paweletz
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  17. Sangeetha Palakurthi
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  18. Joyce F. Liu
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  19. Alan D. D’Andrea
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  21. Dipanjan Chowdhury
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  22. Ursula A. Matulonis
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Contributions

PAK conceived, supervised, coordinated, and analysed all the data and wrote the manuscript; S-CC performed the statistical analysis and was the lead statistician of the study; JGS performed the PK analyses; MP, BB, HS, PB, MH and JC contributed to data collection and coordinated the processing and distribution of the clinical trial samples; AEW, PI, NH, AAW and SMC provided clinical data and contributed to the analysis of data; EVI, CPP, SP, JFL, ADD and DC performed and contributed to the preclinical studies and to the analysis of data; UAM and GIS supported and supervised the analyses of this study. All authors contributed to the writing and editing of the manuscript.

Corresponding author

Correspondence to Panagiotis A. Konstantinopoulos.

Ethics declarations

Ethics approval and consent to participate

The clinical trial was approved by the NCI Central Institutional Review Board (CIRB) and the US Food and Drug Administration (NCT02898207). All procedures involving human participants were carried out in accordance with the Declaration of Helsinki. Written informed consent was obtained from patients or guardians before enrolment in the study.

Consent to publish

Not applicable.

Competing interests

Dr. Konstantinopoulos has participated in advisory boards for Alkermes, AstraZeneca, GSK, BMS, Repare, Artios and Kadmon, serves in the gynaecologic oncology scientific committee for AstraZeneca and has received institutional support as P.I. of clinical trials from AstraZeneca, Bayer, Eli Lilly, GSK, Merck, Merck KGaA, Pfizer and GSK. Dr. Cloud Paweletz has sponsored research agreements with Daiichi Sankyo, Bicycle Therapeutics, Transcenta, Bicara Therapeutics, AstraZeneca, Intellia Therapeutics, Janssen Pharmaceuticals, Array Biopharma, has stock and other ownership Interests in XSphera Biosciences, has received honoraria from Bio-Rad and ThermoFisher and has consulting or advisory role for DropWorks and XSphera Biosciences. Dr. Liu has participated in advisory boards from AstraZeneca, Clovis, Eisai, EpsilaBio, Genentech, GSK/Tesaro, Regeneron Pharmaceuticals and has received institutional support as P.I. of clinical trials from 2X Oncology, Aravive, Arch Oncology, AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, CytomX Therapeutics, GlaxoSmithKline, Regeneron, Surface Oncology, Tesaro, Vigeo therapeutics. Dr. Campos has participated in the advisory board for AstraZeneca. Dr. Wright has participated in the advisory board for GSK. Dr. Matulonis has participated in advisory boards for Novartis, Blueprint Medicines, Trillium, in data safety monitoring boards for Advaxis and Symphogen and has been a consultant for NextCure, Astrazeneca and Merck. Dr. D’Andrea is a consultant/advisory board member for Lilly Oncology, Merck-EMD-Serono, Intellia Therapeutics, Sierra Oncology, Cyteir Therapeutics, Third Rock Ventures, AstraZeneca, Ideaya Inc., Cedilla Therapeutics Inc., a stockholder in Ideaya Inc., Cedilla Therapeutics Inc., and Cyteir, and reports receiving commercial research grants from Lilly Oncology and Merck-EMD-Serono. Dr. Shapiro has received research funding from Eli Lilly, Merck KGaA/EMD-Serono, Merck, and Sierra Oncology, has served on advisory boards for Pfizer, Eli Lilly, G1 Therapeutics, Roche, Merck KGaA/EMD-Serono, Sierra Oncology, Bicycle Therapeutics, Fusion Pharmaceuticals, Cybrexa Therapeutics, Astex, Almac, Ipsen, Bayer, Angiex, Daiichi Sankyo, Seattle Genetics, Boehringer Ingelheim, ImmunoMet, Asana, Artios, Atrin, Concarlo Holdings, Syros, Zentalis, CytomX Therapeutics and Blueprint Medicines and holds a patent entitled, “Dosage regimen for sapacitabine and seliciclib,” also issued to Cyclacel Pharmaceuticals, and a pending patent, entitled, “Compositions and Methods for Predicting Response and Resistance to CDK4/6 Inhibition,” together with Liam Cornell.

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Konstantinopoulos, P.A., Cheng, SC., Supko, J.G. et al. Combined PARP and HSP90 inhibition: preclinical and Phase 1 evaluation in patients with advanced solid tumours. Br J Cancer 126, 1027–1036 (2022). https://doi.org/10.1038/s41416-021-01664-8

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