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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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“In a phase 1b clinical trial, combination treatment of Alpelisib (a PI3K inhibitor) and Olaparib (a PARP inhibitor) resulted in partial response in 10 out of 28 patients with recurrent EOC [20].”
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“Of those with OC treated with the combination of Ola and AZD5363, several patients achieved durable responses (4/6 stable disease (SD) and 1/7 partial response (PR)).”
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“Moreover, combination therapies of PARP inhibitors and PI3K-AKT inhibitors have been found to be effective treatment strategies in several preclinical and clinical trials [21,22].”
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“Alpe-lisib and olaparib were combined in another phase I trial evaluating safety in patients with wildtype or gBRCA1/2 m advanced ovarian cancer, with results showing the combination to be safe with preliminary evidence of efficacy, including in those patients with wildtype BRCA1/2 [15].”
Homologous Recombination Repair in Biliary Tract Cancers: A Prime Target for PARP Inhibition?
Yin, C., Kulasekaran, M., Roy, T., Decker, B. J., Alexander, S., Margolis, M. L., Jha, R. C., Kupfer, G. M., & He, A. R. (2022) · Cancers · doi:10.3390/cancers14102561 · Cited by 9
“An early phase I clinical trial suggested synergy between alpelisib (PI3K inhibitor) and olaparib in ovarian cancer [112].”
BackgroundPatient selection biomarker strategies for PARP inhibitor therapy
Pilie, P. G., George, A. J., & Yap, T. A. (2020) · Annals of Oncology · doi:10.1016/j.annonc.2020.09.017 · Cited by 10
Pharmacological methods to transcriptionally modulate double-strand break DNA repair
Kaplan, A. R., & Glazer, P. M. (2019) · International review of cytology · doi:10.1016/bs.ircmb.2019.11.003 · Cited by 9
“Similar results were found using the combination of the PI3K inhibitor alpelisib with olaparib in epithelial ovarian cancer (Konstantinopoulos et al. 2019).”
ResultZhi, W., Li, S., Wan, Y., Wu, F., & Li, H. (2022) · Cancer Cell International · doi:10.1186/s12935-022-02447-8 · Cited by 9
“Some research has already explored strategies of PARPi combined with VEGFR inhibitors [11], PI3K inhibitors [12], CDK inhibitors [13], PD-L1 blockade [14] and so on, and some of them have entered clinical trials.”
BackgroundLai, W., Xie, R., Chen, C., Lou, W., Yang, H., Deng, L., Lu, Q., & Tang, X. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e28490 · Cited by 8
Targeting tumour markers in ovarian cancer treatment
Preetam, S., Mondal, S., Priya, S., Bora, J., Ramniwas, S., Rustagi, S., Qusty, N. F., Alghamdi, S. A., Babalghith, A. O., Siddiqi, A., et al. (2024) · Clinica Chimica Acta · doi:10.1016/j.cca.2024.119687 · Cited by 8
Iranpanah, A., Majnooni, M. B., Biganeh, H., Amirian, R., Rastegari‐Pouyani, M., Filosa, R., Cheang, W. S., Fakhri, S., & Khan, H. Z. (2024) · Phytotherapy Research · doi:10.1002/ptr.8228 · Cited by 8
“…breast cancer (Maric et al., 2019; McAuliffe et al., 2010; K. Zhu, Wu, et al., 2022), gastric carcinoma (Matsuoka & Yashiro, 2014), ovarian cancer (Konstantinopoulos et al., 2019; Mabuchi et al., 2015; Si et al., 2020), and several other cancer types (Bahrami et al., 2017; Iksen et al., 2021;…”
Molecular characterization of ovarian squamous cell carcinoma originating from mature teratoma
Chao, A., Lai, C., Chao, A.-S., Lin, C., Wang, Y.-C., Huang, H.-J., & Wu, R. (2024) · Journal of Molecular Medicine · doi:10.1007/s00109-024-02505-w · Cited by 8
“Notably, alpelisib has already gained approval for the treatment of PIK3CA -mutated breast cancer [20] and is currently under investigation in ovarian malignancies [21].”
Konstantinopoulos, P. A., Kim, J., Freyer, G., Lee, J., Gaba, L., Grisham, R. N., Colombo, N., Wu, X., Sehouli, J., Cruz, F. J. S. M., et al. (2025) · Journal of Clinical Oncology · doi:10.1200/jco-25-00225 · Cited by 8
Self-citationProteomics advances for precision therapy in ovarian cancer
Labrie, M., Kendsersky, N. D., Ma, H., Campbell, L. G., Eng, J. R., Chin, K., & Mills, G. B. (2019) · Expert Review of Proteomics · doi:10.1080/14789450.2019.1666004 · Cited by 8
“A second adaptive response that has been demonstrated is the activation of pro-survival signaling pathways such as the RAS-MAPK and PI3K pathways [33,44,50,70].”
BackgroundSelf-citationTargeting DNA Homologous Repair Proficiency With Concomitant Topoisomerase II and c-Abl Inhibition
Siddiqui, A., Tumiati, M., Joko, A., Sandholm, J. A., Roering, P., Aakko, S., Vainionpää, R., Kaipio, K., Huhtinen, K., Kauppi, L., et al. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.733700 · Cited by 10
Pham, M. M., Hinchcliff, E., Avila, M., & Westin, S. N. (2021) · The Cancer Journal · doi:10.1097/ppo.0000000000000562 · Cited by 9
Self-citationZSTK474 Sensitizes Glioblastoma to Temozolomide by Blocking Homologous Recombination Repair
Jiao, W., Zhu, S., Shao, J., Zhang, X., Xu, Y., Zhang, Y., Wang, R., Zhong, Y., & Kong, D. (2022) · BioMed Research International · doi:10.1155/2022/8568528 · Cited by 8
Ethier, J.-L., Fuh, K. C., Arend, R. C., Konecny, G. E., Konstantinopoulos, P. A., Odunsi, K. O., Swisher, E. M., Kohn, E. C., & Zamarin, D. (2022) · JCO Precision Oncology · doi:10.1200/po.22.00355 · Cited by 8
Self-citationDey, P., Biswas, S., Das, R., Chatterjee, S., & Ghosh, U. (2023) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2023.05.116 · Cited by 8
Molecular Methods for Increasing the Effectiveness of Ovarian Cancer Treatment: A Systematic Review
Chilimoniuk, Z., Rocka, A. A., Stefaniak, M., Tomczyk, Z., Jasielska, F., Madras, D. K., & Filip, A. A. (2022) · Future Oncology · doi:10.2217/fon-2021-0565 · Cited by 8
Alobid, S. E. (2026) · Saudi Pharmaceutical Journal · doi:10.1007/s44446-025-00056-w · Cited by 12
“Similar outcomes have been recorded with the PI3Kα inhibitor alpelisib combined with the PARP inhibitor olaparib, in whom durable stable disease and objective responses were reported in a group of enrolled patients (Konstantinopoulos et al. 2019).”
Further Understanding of High-Grade Serous Ovarian Carcinogenesis: Potential Therapeutic Targets
Voutsadakis, I. A. (2020) · Cancer Management and Research · doi:10.2147/cmar.s249540 · Cited by 8
“Combining olaparib with the specific PI3Kα inhibitor alpelisib was feasible and was reported in a phase Ib study to have activity in platinum-refractory ovarian cancer patients who had received 2 to 5 previous lines of therapy.(35) Response rate (RR) was 36% (10 of 28 patients), much higher than the RR that would be e…”
BackgroundPrognostic Significance of the CXCLs and Its Impact on the Immune Microenvironment in Ovarian Cancer
Gu, C., Xiong, X., & Liu, W. (2023) · Disease Markers · doi:10.1155/2023/5223657 · Cited by 7
“The diagnosis and treatment of ovarian cancer have made great progress in recent years, such as the emergence of new materials [10 – 12], new drugs [13, 14], and new molecular markers or targets [15].”
Liu, Y., Sun, Q., & Wei, X. (2024) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2024.2342522 · Cited by 8
Rational Combinations of PARP Inhibitors with HRD-Inducing Molecularly Targeted Agents
Lee, E. K., & Liu, J. F. (2023) · Cancer treatment and research · doi:10.1007/978-3-031-30065-3_10 · Cited by 6
Self-citationZhang, Y., Xu, M., Yuan, J., Hu, Z., Jiang, J., Sun, Y., Huang, J. S., Wang, Y., Wang, B., Shen, J., et al. (2024) · eLife · doi:10.7554/elife.99225 · Cited by 8
“…et al., 2014 ) or small molecules that indirectly modulate DDR gene transcription (e.g., PI3KCAi Ibrahim et al., 2012 ; Juvekar et al., 2012 ; Konstantinopoulos et al., 2019 ; Batalini et al., 2022 , AKTi Yap et al., 2020 ; Westin et al., 2021 , mTORi Mo et al., 2016 , and MEKi Sun et al.,…”
InfluentialHarnessing transcriptional regulation of alternative end-joining to predict cancer treatment
Espín, R., Medina‐Jover, F., Sigüenza-Andrade, J., Farran-Matas, S., Mateo, F., Figueras, A., Sanz, R. T., Vicent, G. P., Shabbir, A., Ruiz-Auladell, L., et al. (2025) · NAR Cancer · doi:10.1093/narcan/zcaf007 · Cited by 7
Cathcart, A. M., Smith, H. L., Labrie, M., & Mills, G. B. (2022) · Expert Review of Proteomics · doi:10.1080/14789450.2022.2070065 · Cited by 6
“monotherapy in patients with BRCA-wild type platinumresistant ovarian cancer have shown an overall response rate (ORR) around 5%, a recent Phase 1b trial including 26 platinum-resistant or refractory ovarian cancer patients treated with combination olaparib and the PI3K inhibitor (PI3Ki) alpelisib showed an ORR of 33%…”
BackgroundSelf-citationTargeting Adaptation to Cancer Treatment by Drug CombinationsPreprint
Wang, H., Luna, A., Yan, G., Li, X., Babur, Ö., Mills, G. B., Sander, C., & Korkut, A. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.04.14.439861 · Cited by 5
Self-citationBCL-2 Family Inhibition Enhances mTORC1/2 Inhibition in PIK3CA -Mutant Colorectal Cancer
DeStefanis, R. A., Schmitz, A. E., Steimle, A. K., Payne, S. N., Sha, G. C., Olson, A. M., Cornelio, A. B., Lippert, A. E. L., Kraus, S. G., Johnson, K. A., et al. (2025) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-24-1096 · Cited by 4
Enhancing PARP inhibitor efficacy in ovarian cancer: targeting the PI3K/AKT/mTOR pathway
Wang, Y., Xia, Q., Wang, X., Lu, Y., Wang, S., & Jiao, Y. (2025) · Journal of Ovarian Research · doi:10.1186/s13048-025-01868-z · Cited by 4
“Molecular stratification using PIK3CA/PTEN status, HRD scores, or phospho-AKT levels can identify patients at risk [67, 220].”
InfluentialDuffield, J. R., Hou, X., Wilson, B. W., Prasad, A., McKeon-Makki, I. K., Huehls, A. M., Wu, X., Correia, C., Larson, M. C., Couch, F. J., et al. (2026) · Science Translational Medicine · doi:10.1126/scitranslmed.adt8706 · Cited by 5
Self-citationZhang, Y., Gao, S., Mao, J., Song, Y., Wang, X., Jiang, J., Li, Z., Zhou, Z., & Wang, J. (2024) · Molecules · doi:10.3390/molecules29215214 · Cited by 4
Li, Y., Li, H., & Xiang, Z. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e27599 · Cited by 4
“A phase 1b trial confirmed the occurrence of PTs as described above, consistent with our results [22].”
ResultThibault, B., Thole, A., D’Angelo, R., Basset, C., & Guillermet‐Guibert, J. (2025) · Scientific Reports · doi:10.1038/s41598-025-90714-9 · Cited by 4
“A phase 1b clinical trial testing Olaparib in combination with BYL-719/Alpelisib observes preliminary clinical evidence of synergism between these two inhibitors, in patients with indication for Olaparib treatment 50 .”
Hiroki, H., Akahane, K., Inukai, T., Morio, T., & Takagi, M. (2022) · International Journal of Hematology · doi:10.1007/s12185-022-03520-8 · Cited by 5
“In a clinical setting, the results of a Phase I study using olaparib and the PI3Ki, alpelisib, for treatment of patients with epithelial ovarian cancer revealed that this combination is feasible, and its observed activity provided preliminary clinical evidence of synergy between olaparib and alpelisib [45].”
Unifying targeted therapy for leukemia in the era of PARP inhibition
Boila, L. D., & Sengupta, A. (2023) · Experimental Hematology · doi:10.1016/j.exphem.2023.05.005 · Cited by 4
He, Z., Gao, Y., Li, T., Yu, C., Ou, L., & Luo, C. (2022) · International Journal of Oncology · doi:10.3892/ijo.2022.5327 · Cited by 5
“67 35 (53) 22 (33) 13 (20) 9 (14) 26 (39)”
BackgroundAutophagy inhibition enhances sensitivity of alpelisib in PI3K–mutated non-small cell lung cancer
Kim, J., Shrestha, C., Kim, T. W., Lee, S.-B., Lee, G., Jung, D., Hwang, M., Kang, S., Park, H. S., Kim, H., et al. (2025) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2025.118620 · Cited by 4
The PIK3CA/AKT pathway drives therapy resistance in rhabdomyosarcoma
Yang, Q., Wang, Y., Corchete, L. A., Mathavarajah, S., Qin, Q., Wei, Y., Alpert, E. J., Whelton, L. R., Sharma, P., Strom, S., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-66632-9 · Cited by 3
“Doses administered for Olaparib, temozolomide, and Alpelisib were selected based on previous published xenograft and clinical trial studies 13,81,82,92,93 .”
Bayram, E., Khatib, G., Güney, İ. B., Bağır, E. K., Gulec, H. R., Boğa, İ., & Paydaş, S. (2023) · Genes · doi:10.3390/genes14081632 · Cited by 3
“Multicenter, open-label, phase Ib trial [28], NCT01623349 recurrent ovarian, fallopian tube, primary peritoneal, or breast cancer BRCA The starting oral dose level: 1 × 250 mg/day alpelisib + 2 × 100 mg/day olaparib.”
BackgroundDesign of PI3K-mTOR Dual Inhibitors for Ovarian Cancer: Are we on the Right Track?
Mangala, S. S., Rathi, E., Udupa, K., Kabekkodu, S. P., Pai, K. S. R., & Kini, S. G. (2024) · Current Medicinal Chemistry · doi:10.2174/0109298673293028240326051835 · Cited by 4
Pharmacological PI3K inhibition in head and neck squamous cell carcinoma: A systematic review
Alves, L., Moura, A., dos Santos, J. A., Borges, G. Á., & Guerra, E. N. S. (2023) · Toxicology in Vitro · doi:10.1016/j.tiv.2023.105558 · Cited by 3
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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