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.
“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]
The Introduction (page unavailable) says PI3K inhibition increases DNA damage and sensitizes cancer cells to PARP inhibitors. Neither it nor the retrieved passages on the olaparib–alpelisib combination say that olaparib-induced DNA damage activates PI3K/AKT as a survival mechanism. Searches for that proposed activation and for AKT activation after PARP inhibition found no supporting passage in our copy. (LLM, conf=0.72)
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“with the -specific PI3K inhibitor alpelisib (15).”
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BackgroundClinical approaches to overcome PARP inhibitor resistance
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“In addition, combining alpelisib and olaparib is feasible with no unexpected toxic effects, and the common adverse effects are hyperglycemia and nausea [118] (Table 4).”
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“agents which directly or indirectly inhibit HRR, is a promising strategy to overcome acquired PARPi resistance in HRR-deficient tumours as well as de novo PARPi resistance in HRR-proficient tumours [2, 3].”
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“Data from early phase demonstrate an efficacy (ORR 36%) of olaparib and the α specific PI3K inhibitor apelisib, which provides preliminary clinical evidence of synergism between olaparib and alpelisib, particularly in EOC [98].”
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“Preclinical studies have shown that PI3K inhibitors may impair homologous recombination repair and sensitize ovarian cancer cells to PARP inhibitors.(98) Results from a phase Ib combination study of alpelisib with olaparib, in patients with recurrent ovarian cancer after prior platinum-based therapy, indicated a parti…”
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“responses in 36% and stable disease in 50% of 28 patients with BRCA wild-type OC(Konstantinopoulos et al., 2019).”
BackgroundUpdate on Combination Strategies of PARP Inhibitors
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“48 In a phase IIb clinical trial, 17 patients with recurrent breast cancer, including those with TNBC and other subtypes, were selected based on their germline BRCA mutation status.”
BackgroundStrategies in Overcoming Homologous Recombination Proficiency and PARP Inhibitor Resistance
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PARP Inhibitors: Strategic Use and Optimal Management in Ovarian Cancer
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“Olaparib and alpelisib, a PI3K inhibitor that is also part of the homologous recombination repair pathway, reported an ORR of 36% [24].”
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“Olaparib and alpelisib, a PI3K-alpha inhibitor, were combined in a multicenter, open-label, phase Ib trial in the 28 recurrent EOC patients with high-grade serous histology, and 36% of participants achieved partial response and 50% showed stable disease [264].”
MethodParp Inhibitors: A Tsunami of Indications in Different Malignancies
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PARPi after PARPi in epithelial ovarian cancer
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“%) had mixed EOC (one with mixed high grade serous and high grade endometrioid, and the other with mixed high grade endometrioid and clear cell EOC).”
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Combination Treatment Strategies to Overcome PARP Inhibitor Resistance
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“%) monotherapy in patients with platinum-resistant epithelial ovarian cancer [89].”
BackgroundPARP Inhibitors in Gynecologic Cancers: What Is the Next Big Development?
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“The synergistic activity between alpelisib and olaparib in platinum-resistant HGSOC of the BRCA wild-type has been shown in an EPIK-O/ENGOT-OV16 study, thereby extending the potential use of PARPis beyond the HRR-deficient context [115,133,134].”
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“Other studies have explored combinations of alpesilib with olaparib and erdafitinib with check point inhibitors (29,40).”
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“tions of PARPi with PI3K pathway inhibitors and combinations of PARPi and VEGFR inhibitors such as cediranib [37,38].”
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“The combination of alpelisib and olaparib has been shown to exhibit a synergistic effect against BRCA wild-type, platinum-resistant OC [52].”
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“The efficacy and safety of the combination therapy, including PARP inhibitors plus angiogenesis inhibitors (6,7), immune checkpoint inhibitors (8-10), cyclin dependent kinase (CDK) 4/6 inhibitors (11,12), phosphoinositide 3-kinase (PI3K) inhibitors (13), protein kinase B (AKT) inhibitors (14), mammalian target of rapa…”
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Targeting PARP for the optimal immunotherapy efficiency in gynecologic malignancies
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- 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 › Reproductive Medicine › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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