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Olaparib and α-specific PI3K inhibitor alpelisib for patients with epithelial ovarian cancer: a dose-escalation and dose-expansion phase 1b trial
Open accessAbstract
Background Based on preclinical work, we found that combination of poly (ADP-ribose) polymerase (PARP) inhibitors with drugs that inhibit the homologous recombination repair (HRR) pathway (such as PI3K inhibitors) might sensitise HRR-proficient epithelial ovarian cancers to PARP inhibitors. We aimed to assess the safety and identify the recommended phase 2 dose of the PARP inhibitor olaparib in combination with the PI3K inhibitor alpelisib in patients with epithelial ovarian cancer and in patients with breast cancer. Methods In this multicentre, open-label, phase 1b trial following a 3 + 3 dose-escalation design, we recruited patients aged 18 years or older with the following key eligibility criteria: confirmed diagnosis of either recurrent ovarian, fallopian tube, or primary peritoneal cancer of high-grade serous histology; confirmed diagnosis of either recurrent ovarian, fallopian tube, or primary peritoneal cancer of any histology with known germline BRCA mutations; confirmed diagnosis of recurrent breast cancer of triple-negative histology; or confirmed diagnosis of recurrent breast cancer of any histology with known germline BRCA mutations. Additional patients with epithelial ovarian cancer were enrolled in a dose-expansion cohort. Four dose levels were planned: the starting dose level of alpelisib 250 mg once a day plus olaparib 100 mg twice a day (dose level 0); alpelisib 250 mg once a day plus olaparib 200 mg twice a day (dose level 1); alpelisib 300 mg once a day plus olaparib 200 mg twice a day (dose level 2); and alpelisib 200 mg once a day plus olaparib 200 mg twice a day (dose level 3). Both drugs were administered orally, in tablet formulation. The primary objective was to identify the maximum tolerated dose and the recommended phase 2 dose of the combination of alpelisib and olaparib for patients with epithelial ovarian cancer and patients with breast cancer. Analyses included all patients who received at least one dose of the study drugs. The trial is active, but closed to enrolment; follow-up for patients who completed treatment is ongoing. This trial is registered with ClinicalTrials.gov, number NCT01623349. Findings Between Oct 3, 2014, and Dec 21, 2016, we enrolled 34 patients (28 in the dose-escalation cohort and six in the dose-expansion cohort); two in the dose-escalation cohort were ineligible at the day of scheduled study initiation. Maximum tolerated dose and recommended phase 2 dose were identified as alpelisib 200 mg once a day plus olaparib 200 mg twice a day (dose level 3). Considering all dose levels, the most common treatment-related grade 3-4 adverse events were hyperglycaemia (five [16%] of 32 patients), nausea (three [9%]), and increased alanine aminotransferase concentrations (three [9%]). No treatment-related deaths occurred. Dose-limiting toxic effects included hyperglycaemia and fever with decreased neutrophil count. Of the 28 patients with epithelial ovarian cancer, ten (36%) achieved a partial response and 14 (50%) had stable disease according to Response Evaluation Criteria in Solid Tumors 1.1. Interpretation Combining alpelisib and olaparib is feasible with no unexpected toxic effects. The observed activity provides preliminary clinical evidence of synergism between olaparib and alpelisib, particularly in epithelial ovarian cancer, and warrants further investigation. Funding Ovarian Cancer Dream Team (Stand Up To Cancer, Ovarian Cancer Research Alliance, National Ovarian Cancer Coalition), Breast Cancer Research Foundation, Novartis.
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“In cancer cells, the PI3K/AKT pathway may be activated as a survival mechanism in response to the DNA damage caused by olaparib.”
From Celastrol attenuates the invasion and migration and augments the anticancer effects of olaparib in prostate cancer (2024) · cites this paper as [41]
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Citations
Cites
Integrated genomic analyses of ovarian carcinoma
Perou, C. M. (2019) · Carolina Digital Repository (University of North Carolina at Chapel Hill) · doi:10.17615/hvp3-wg08 · Cited by 7,927
Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer
Moore, K., Colombo, N., Scambia, G., Kim, B.-G., Oaknin, A., Friedlander, M., Lisyanskaya, A., Floquet, A., Leary, A., Sonke, G. S., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1810858 · Cited by 2,870 · cited 1×
“Finally, although nausea, fatigue and vomiting were observed in 50% or more of patients, these toxicities were mostly grade 1 and 2, easily manageable, and comparable to those observed with olaparib monotherapy (77% nausea, 63% fatigue and 40% vomiting in the recently reported SOLO1 study(22)).”
ResultSelf-citationNiraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer
Mirza, M. R., Monk, B. J., Herrstedt, J., Oza, A. M., Mahner, S., Redondo, A., Fabbro, M., Ledermann, J. A., Lorusso, D., Vergote, I. B., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1611310 · Cited by 2,452
Self-citationAudeh, M. W., Carmichael, J., Penson, R. T., Friedlander, M., Powell, B., Bell-McGuinn, K. M., Scott, C., Weitzel, J. N., Oaknin, A., Loman, N., et al. (2010) · The Lancet · doi:10.1016/s0140-6736(10)60893-8 · Cited by 2,279
Self-citationPujade-Lauraine, É., Hilpert, F., Weber, B. E., Reuß, A., Poveda, A. M., Kristensen, G. B., Sorio, R., Vergote, I. B., Witteveen, P. O., Bamias, A., et al. (2014) · Journal of Clinical Oncology · doi:10.1200/jco.2013.51.4489 · Cited by 1,660 · cited 1×
“The median duration of response and median PFS and OS observed in this population were also promising and in line with the results of AURELIA study in platinum resistant ovarian cancer (27) despite the fact that AURELIA involved a significantly less heavily pretreated patient population as it allowed patients with onl…”
ResultSwisher, E. M., Lin, K. K., Oza, A. M., Scott, C. L., Giordano, H., Sun, J., Konecny, G. E., Coleman, R. L., Tinker, A. V., O'Malley, D. M., et al. (2017) · The Lancet Oncology · doi:10.1016/s1470-2045(16)30559-9 · Cited by 1,196 · cited 1×
“The promise of PARPis in the management of EOC is tempered, however, by the fact that EOCs with intrinsic, de novo, HRR proficiency respond less than HRR-deficient carcinomas (5, 6).”
BackgroundSelf-citationGelmon, K. A., Tischkowitz, M. D., MacKay, H. J., Swenerton, K. D., Robidoux, A., Tonkin, K. S., Hirte, H. W., Huntsman, D. D., Clemons, M. J., Gilks, C. B., et al. (2011) · The Lancet Oncology · doi:10.1016/s1470-2045(11)70214-5 · Cited by 1,130 · cited 4×
“The promise of PARPis in the management of EOC is tempered, however, by the fact that EOCs with intrinsic, de novo, HRR proficiency respond less than HRR-deficient carcinomas (5, 6).”
BackgroundInfluentialSecondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers
Sakai, W., Swisher, E. M., Karlan, B. Y., Agarwal, M. K., Higgins, J., Friedman, C., Villegas, E., Jacquemont, C., Farrugia, D. J., Couch, F. J., et al. (2008) · Nature · doi:10.1038/nature06633 · Cited by 1,086
Self-citationFong, P. C. C., Yap, T. A., Boss, D. S., Carden, C. P., Mergui‐Roelvink, M., Gourley, C., Grève, J. D., Lubiński, J., Shanley, S., Messiou, C., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.26.9589 · Cited by 1,022
Homologous Recombination Deficiency: Exploiting the Fundamental Vulnerability of Ovarian Cancer
Konstantinopoulos, P. A., Ceccaldi, R., Shapiro, G. I., & D'Andrea, A. D. (2015) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-0714 · Cited by 945
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The PI3K–AKT network at the interface of oncogenic signalling and cancer metabolism
Hoxhaj, G., & Manning, B. D. (2020) · Nature Reviews Cancer · doi:10.1038/s41568-019-0216-7 · Cited by 2,137
PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer
Glaviano, A., Foo, A. S. C., Lam, H. Y., Yap, K. C. H., Jacot, W., Jones, R. H., Eng, H., Nair, M. G., Makvandi, P., Geoerger, B., et al. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01827-6 · Cited by 2,138
“therapy in breast cancer [228] and other advanced solid tumors [229, 230], as well as in combination with either trastuzumab-emtansine [231], fulvestrant [232–235], letrozole [236–239], nab-paclitaxel [240], olaparib [241], or trastuzumab + LJM716 [242], in breast cancer, and in combination with either imatinib [243],…”
BackgroundRecent advances in therapeutic strategies for triple-negative breast cancer
Li, Y., Zhang, H., Merkher, Y., Chen, L., Liu, N., Leonov, S. V., & Chen, Y. (2022) · Journal of Hematology & Oncology · doi:10.1186/s13045-022-01341-0 · Cited by 1,035
Attacking the PI3K/Akt/mTOR signaling pathway for targeted therapeutic treatment in human cancer
Yu, L., Wei, J., & Liu, P. (2021) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.06.019 · Cited by 818
PARP and PARG inhibitors in cancer treatmentPreprint
Slade, D. (2020) · Genes & Development · doi:10.1101/gad.334516.119 · Cited by 693
“A phase I clinical trial revealed synergistic effects between olaparib and the PI3K inhibitor alpelisib in epithelial ovarian cancer, which are most likely based on HR suppression through reduced RAD51 protein levels and RAD51 foci formation (Konstantinopoulos et al. 2019).”
Metadata
- Authors
- Konstantinopoulos, P. A., Barry, W. T., Birrer, M., Westin, S. N., Cadoo, K. A., Shapiro, G. I., Mayer, E. L., O'Cearbhaill, R. E., Coleman, R. L., Kochupurakkal, B., Whalen, C., Curtis, J., Farooq, S., Luo, W., Eismann, J., Buss, M. K., Aghajanian, C., Mills, G. B., Palakurthi, S., Kirschmeier, P., Liu, J., Cantley, L. C., Kaufmann, S. H., Swisher, E. M., D'Andrea, A. D., Winer, E., Wulf, G. M., & Matulonis, U. A.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Massachusetts General Hospital (US)
- The University of Texas MD Anderson Cancer Center (US)
- Memorial Sloan Kettering Cancer Center (US)
- Beth Israel Deaconess Medical Center (US)
- Oregon Health & Science University (US)
- Weill Cornell Medicine (US)
- Mayo Clinic (US)
- University of Washington (US)
- Corresponding author
- Konstantinopoulos, Panagiotis A
- ORCID
- Konstantinopoulos, Panagiotis A
- Birrer, Michael
- Westin, Shannon N
- Cadoo, Karen A
- Shapiro, Geoffrey I
- Mayer, Erica L
- O'Cearbhaill, Roisin E
- Coleman, Robert L
- Kochupurakkal, Bose
- Farooq, Sarah
- Buss, Mary K
- Aghajanian, Carol
- Mills, Gordon B
- Palakurthi, Sangeetha
- Liu, Joyce
- Cantley, Lewis C
- Kaufmann, Scott H
- Swisher, Elizabeth M
- Winer, Eric
- Wulf, Gerburg M
- Matulonis, Ursula A
- Venue
- The Lancet Oncology
- Publisher
- Elsevier BV
- Published
- 2019-04
- Volume
- 20
- Issue
- 4
- Pages
- 570-580
- ISSN
- 1470-2045 (ISSN-L)
- PMC
- PMC7025391
- OpenAlex
- W2921991537
- Cited by
- 263
- References
- 33
- Citations by year
- 2026: 13 · 2025: 29 · 2024: 33 · 2023: 38 · 2022: 48 · 2021: 46 · 2020: 38 · 2019: 17
- FWCI
- 15.67
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Lancet Oncology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Breast Cancer Research Foundation
- Topics
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Health Sciences › Medicine › Oncology › Ovarian cancer diagnosis and treatment
- Keywords
- olaparib, alpelisib, PI3K inhibitors, PARP inhibitors, epithelial ovarian cancer, breast cancer, triple-negative breast cancer, homologous recombination repair, BRCA mutations, high-grade serous ovarian cancer, combination therapy, maximum tolerated dose, recommended phase 2 dose, drug safety, dose escalation, dose expansion, recurrent cancer, PARP inhibitor resistance
- MeSH terms
- Poly(ADP-ribose) Polymerase Inhibitors, Carcinoma, Ovarian Epithelial, Phosphoinositide-3 Kinase Inhibitors, Aged, Antineoplastic Combined Chemotherapy Protocols, Dose-Response Relationship, Drug, Female, Humans, Middle Aged, Mutation, Ovarian Neoplasms, Phthalazines, Piperazines, Thiazoles, Genome, Human, Treatment Outcome, Maximum Tolerated Dose, Drug-Related Side Effects and Adverse Reactions
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