Alpelisib Plus Olaparib in Platinum-resistant/Refractory, High-grade Serous Ovarian Cancer, With no Germline BRCA Mutation Detected

EPIK-O: A Phase III, Multi-center, Randomized (1:1), Open-label, Active-controlled, Study to Assess the Efficacy and Safety of Alpelisib (BYL719) in Combination With Olaparib as Compared to Single Agent Cytotoxic Chemotherapy, in Participants With no Germline BRCA Mutation Detected, Platinum-resistant or Refractory, High-grade Serous Ovarian Cancer

The objective of this study was to assess the efficacy and safety of the combination of alpelisib and olaparib compared with single agent cytotoxic chemotherapy in patients with platinum resistant or refractory high-grade serous ovarian cancer, with no germline BRCA mutation detected.

Study Overview

• Status: Terminated
• Conditions: Ovarian Cancer
• Intervention / Treatment: Drug: Alpelisib; Drug: Olaparib; Drug: Paclitaxel; Drug: Pegylated liposomal doxorubicin (PLD)

Detailed Description

This study included adult women with platinum resistant or refractory high-grade serous ovarian cancer, with no germline BRCA mutation detected. Participants were randomized in a 1:1 ratio to either alpelisib plus olaparib or single agent cytotoxic chemotherapy (paclitaxel or PLD) in this open-label, active controlled study.

Participants continued to receive study treatment until disease progression, unacceptable toxicity that precludes further treatment, or until discontinuation of study treatment due to any other reason. After treatment discontinuation, all participants entered in the post-treatment follow-up period, which consisted of a safety follow-up visit and a 9-week post-progression visit. Once they completed the post-treatment follow-up, participants then entered the survival follow-up period.

• Study Type: Interventional
• Enrollment (Actual): 358
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1012AAR
    • Novartis Investigative Site
  • Caba, Argentina, C1015ABO
    • Novartis Investigative Site
  • Buenos Aires
    • CABA, Buenos Aires, Argentina, C1125ABD
      • Novartis Investigative Site
• Australia
  • Sydney, Australia, 2031
    • Novartis Investigative Site
  • South Australia
    • Bedford Park, South Australia, Australia, 5041
      • Novartis Investigative Site
  • Victoria
    • Shepparton, Victoria, Australia, 3630
      • Novartis Investigative Site
• Austria
  • Graz, Austria, 8036
    • Novartis Investigative Site
  • Tyrol
    • Innsbruck, Tyrol, Austria, 6020
      • Novartis Investigative Site
• Belgium
  • Brussels, Belgium, 1000
    • Novartis Investigative Site
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
  • Namur, Belgium, 5000
    • Novartis Investigative Site
• Brazil
  • Minas Gerais
    • Belo Horizonte, Minas Gerais, Brazil, 30130-100
      • Novartis Investigative Site
  • São Paulo
    • São Paulo, São Paulo, Brazil, 04014-002
      • Novartis Investigative Site
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 5G2
      • Novartis Investigative Site
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • Novartis Investigative Site
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • Novartis Investigative Site
    • Toronto, Ontario, Canada, M4N 3M5
      • Novartis Investigative Site
• China
  • Beijing, China, 100036
    • Novartis Investigative Site
  • Jinan, China, 250012
    • Novartis Investigative Site
  • Shanghai, China, 200032
    • Novartis Investigative Site
  • Tianjin, China, 300480
    • Novartis Investigative Site
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • Novartis Investigative Site
• Czechia
  • Nový Jičín, Czechia, 741 01
    • Novartis Investigative Site
  • Prague, Czechia, 128 08
    • Novartis Investigative Site
  • Poruba
    • Ostrava, Poruba, Czechia, 708 52
      • Novartis Investigative Site
• Denmark
  • Herlev, Denmark, DK-2730
    • Novartis Investigative Site
  • Odense C, Denmark, 5000
    • Novartis Investigative Site
• Finland
  • Kuopio, Finland, FIN-70211
    • Novartis Investigative Site
  • Tampere, Finland, FIN-33521
    • Novartis Investigative Site
  • Turku, Finland, FIN 20521
    • Novartis Investigative Site
• France
  • Besançon, France, 25030
    • Novartis Investigative Site
  • Lyon, France, 69373
    • Novartis Investigative Site
  • Paris, France, 75012
    • Novartis Investigative Site
  • Pierre-Bénite, France, 69495
    • Novartis Investigative Site
  • Villejuif, France, 94800
    • Novartis Investigative Site
• Germany
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Essen, Germany, 45136
    • Novartis Investigative Site
  • Baden-Wurttemberg
    • Mannheim, Baden-Wurttemberg, Germany, 68305
      • Novartis Investigative Site
  • Saxony
    • Dresden, Saxony, Germany, 01307
      • Novartis Investigative Site
• Italy
  • Milan, Italy, 20141
    • Novartis Investigative Site
  • Naples, Italy, 80131
    • Novartis Investigative Site
  • BO
    • Bologna, BO, Italy, 40138
      • Novartis Investigative Site
  • FI
    • Florence, FI, Italy, 50134
      • Novartis Investigative Site
  • MI
    • Milan, MI, Italy, 20133
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00168
      • Novartis Investigative Site
  • VI
    • Vicenza, VI, Italy, 36100
      • Novartis Investigative Site
• Malaysia
  • Kuala Lumpur, Malaysia, 59100
    • Novartis Investigative Site
  • Kuala Lumpur
    • Kuala Lumpur, Kuala Lumpur, Malaysia, 50586
      • Novartis Investigative Site
  • Sabah
    • Kota Kinabalu, Sabah, Malaysia, 88996
      • Novartis Investigative Site
  • Sarawak
    • Kuching, Sarawak, Malaysia, 93586
      • Novartis Investigative Site
• Mexico
  • Mexico City, Mexico, 04700
    • Novartis Investigative Site
  • Nuevo León
    • Monterrey, Nuevo León, Mexico, 64460
      • Novartis Investigative Site
• Netherlands
  • Eindhoven, Netherlands, 5623 EJ
    • Novartis Investigative Site
• Portugal
  • Loures, Portugal, 2674-514
    • Novartis Investigative Site
  • Porto, Portugal, 4200-072
    • Novartis Investigative Site
• Russia
  • Arkhangelsk, Russia, 163045
    • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 119074
    • Novartis Investigative Site
  • Singapore, Singapore, 168583
    • Novartis Investigative Site
• Slovakia
  • Bratislava, Slovakia, 83310
    • Novartis Investigative Site
• South Korea
  • Seoul, South Korea, 03080
    • Novartis Investigative Site
  • Seoul, South Korea, 03722
    • Novartis Investigative Site
• Spain
  • Barcelona, Spain, 08035
    • Novartis Investigative Site
  • Barcelona, Spain, 08036
    • Novartis Investigative Site
  • Córdoba, Spain, 14004
    • Novartis Investigative Site
  • Madrid, Spain, 28034
    • Novartis Investigative Site
  • Valencia, Spain, 46010
    • Novartis Investigative Site
  • Navarre
    • Pamplona, Navarre, Spain, 31008
      • Novartis Investigative Site
• Taiwan
  • Taichung, Taiwan, 407219
    • Novartis Investigative Site
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
  • Taipei, Taiwan, 11217
    • Novartis Investigative Site
• Turkey (Türkiye)
  • Ankara, Turkey (Türkiye), 06520
    • Novartis Investigative Site
  • Karsiyaka
    • Izmir, Karsiyaka, Turkey (Türkiye), 35575
      • Novartis Investigative Site
  • Sihhiye-Altindag
    • Ankara, Sihhiye-Altindag, Turkey (Türkiye), 06230
      • Novartis Investigative Site
  • Yuregir
    • Adana, Yuregir, Turkey (Türkiye), 01230
      • Novartis Investigative Site
• United Kingdom
  • Glasgow, United Kingdom, G12 0YN
    • Novartis Investigative Site
  • London, United Kingdom, SE1 9RT
    • Novartis Investigative Site
  • Manchester, United Kingdom, M20 2BX
    • Novartis Investigative Site
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Arizona Oncology Associates
    • Phoenix, Arizona, United States, 85016
      • HonorHealth
  • Florida
    • Fort Myers, Florida, United States, 33901
      • Florida Cancer Specialists
    • West Palm Beach, Florida, United States, 33401
      • Florida Cancer Specialists
  • Maryland
    • Silver Spring, Maryland, United States, 20904
      • Maryland Oncology Hematology P A
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Dana Farber Cancer Institute
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Ctr
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati
    • Cincinnati, Ohio, United States, 45242
      • Oncology Hematology Care Inc
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57106
      • Avera Cancer Institute
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology
  • Texas
    • Amarillo, Texas, United States, 79124
      • Texas Oncology
    • Bedford, Texas, United States, 76022
      • Texas Oncology P A
    • San Antonio, Texas, United States, 78217
      • Texas Oncology P A
    • Tyler, Texas, United States, 75702
      • Texas Oncology Northeast Texas

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Participant has histologically confirmed diagnosis of high-grade serous or high-grade endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer
• Measurable disease, i.e., at least one measurable lesion per RECIST 1.1 criteria (a lesion at a previously irradiated site may only be counted as a target lesion if there is clear sign of progression since the irradiation)
• If no measurable disease is present, the disease should be assessable by Gynecologic Cancer Intergroup criteria (GCIC) for CA-125
• Participant has no germline BRCA1/2 mutation as determined by an FDA-approved assay
• Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Participant has platinum-resistant (progression within one to six months after completing platinum-based therapy) or platinum refractory disease (progression during treatment or within 4 weeks after the last dose), where platinum-based therapy is not an option, according to the GCIG 5th Ovarian Cancer Consensus Conference definitions (Wilson et al 2016). The platinum-based chemotherapy regimen does not necessarily need to be the last regimen the participant received prior to study entry
• Participant must have received at least one but no more than three prior systemic treatment regimens and for whom single-agent chemotherapy is appropriate as the next line of treatment
• Participant has received prior bevacizumab or is not eligible to receive bevacizumab due to medical reasons.

Key Exclusion Criteria:

• Participant has received prior treatment with any PI3K, mTOR or AKT inhibitor
• Participant is concurrently using other anti-cancer therapy
• Participant is in a state of small or large bowel obstruction or has other impairment of gastrointestinal (GI) function or GI disease
• Participant has had surgery within 14 days prior to starting study drug or has not recovered from major adverse effects
• Participant has not recovered from all toxicities related to prior anticancer therapies to baseline or NCI CTCAE Version 4.03 Grade ≤1. Exception to this criterion: participants with any grade of alopecia are allowed to enter the study
• Participant has an established diagnosis of diabetes mellitus type I or uncontrolled type II based on fasting plasma glucose and HbA1c
• Participants with liver impairment and Child Pugh score B or C
• Participant has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to randomization, and who has not recovered to baseline, grade 1 or better from related adverse effects of such therapy (with the exception of alopecia)
• Participant has a known hypersensitivity to any of the study drugs or excipients
• Participant has a history of myelodysplastic syndrome or acute myeloid leukemia, or presents clinical and/ or laboratory features suggestive thereof.

Other inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Alpelisib+olaparib; Alpelisib (200 mg once daily after food) and Olaparib (200 mg twice daily) were both administered orally on a continuous dosing schedule starting on Cycle 1 Day 1 in a 28-day cycle.	Drug: Alpelisib; Alpelisib was administered at 200 mg orally once daily following food on a continuous dosing schedule starting on Cycle 1 Day 1 in a 28-day cycle; Other Names: BYL719; Drug: Olaparib; Olaparib was administered at 200 mg orally twice daily irrespective of meals on a continuous dosing schedule starting on Cycle 1 Day 1 in a 28-day cycle.
Active Comparator: Paclitaxel or Pegylated liposomal doxorubicin; Paclitaxel (80 mg/m²) was administered as a weekly intravenous infusion on Days 1, 8, 15, and 22 of each 28-day cycle, or Pegylated liposomal doxorubicin (40-50 mg/m² at physician discretion) was administered as an intravenous infusion once every 28 days starting on Cycle 1 Day 1.	Drug: Paclitaxel; Paclitaxel (80 mg/m²) was administered as a weekly intravenous infusion on Days 1, 8, 15, and 22 of each 28-day cycle.; Drug: Pegylated liposomal doxorubicin (PLD); Pegylated liposomal doxorubicin (40-50 mg/m² at physician discretion) was administered as an intravenous infusion once every 28 days starting on Cycle 1 Day 1.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS) Based on Blinded Independent Review Committee (BIRC) Assessment Using RECIST 1.1 Criteria	Progression-free survival (PFS) was defined as the time from randomization to the first documented disease progression or death from any cause, as determined by blinded independent review committee (BIRC) assessment. Participants without an event were censored at the date of their last adequate tumor assessment. Clinical deterioration without objective radiologic evidence was not considered disease progression in the primary efficacy analysis. Disease progression was defined according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, as a ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (including baseline), with an absolute increase of at least 5 mm, the appearance of one or more new lesions, or unequivocal progression of non-target lesions.	From randomization until the date of the first documented progression or death due to any cause, whichever comes first, assessed up to approximately 21 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Overall survival (OS) is defined as the time from date of randomization to date of death due to any cause. If a participant is not known to have died, then OS will be censored at the latest date the participant was known to be alive	From randomization until death, assessed up to approximately 44 months
Overall Response Rate (ORR) With Confirmed Response Based on BIRC Assessment According to RECIST 1.1 Criteria	Overall Response Rate (ORR) was defined as the proportion of participants with best overall response (BOR) of complete response (CR) or partial response (PR) by blinded independent review committee (BIRC) assessment as per RECIST 1.1 criteria: CR = Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm.; PR = At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.	Up to approximately 21 months
Clinical Benefit Rate (CBR) With Confirmed Response Based on BIRC Assessment According to RECIST 1.1	Clinical benefit rate (CBR) with confirmed response was defined as the percentage of participants whose best overall response was a confirmed CR or PR, or stable disease (SD) maintained for at least 24 weeks. CR, PR, and SD were determined by BIRC according to RECIST 1.1 criteria.	Up to approximately 21 months
Time to Response (TTR) Based on BIRC Assessment and According to RECIST 1.1	Time to response (TTR) was defined as the interval from randomization to the first documented occurrence of either complete response (CR) or partial response (PR), which was subsequently confirmed (using the date of initial response, not the confirmation date). CR and PR were determined based on tumor response data assessed by BIRC according to RECIST 1.1 criteria.	From the date of randomization to the first documented response, assessed through Month 12
Duration of Response (DOR) With Confirmed Response Based on BIRC Assessment and According to RECIST 1.1	Duration of response (DOR) with confirmed response was calculated only for participants whose best overall response was a confirmed complete response (CR) or confirmed partial response (PR), based on tumor response data assessed by BIRC according to RECIST 1.1. The start date was the date of the first documented CR or PR (i.e., the initial response date, not the confirmation date), and the end date was the date of first documented disease progression or death due to underlying cancer. Participants without progression or cancer-related death were censored at the date of their last adequate tumor assessment.	From first documented response to first documented progression or death, assessed up to approximately 21 months
Time to Definitive Deterioration of the Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)	Performance status (PS) was evaluated using the ECOG scale, which comprises six grades (0 to 5), where 0 represents fully active and 5 represents death. Time to definitive deterioration in ECOG PS was defined as the interval from randomization to the date when ECOG PS worsened by at least one category from baseline and remained worsened. Deterioration was considered definitive if there was no subsequent improvement to the baseline category or better. Participants were censored if no definitive deterioration occurred before the earlier of: (i) the analysis cut-off date or (ii) initiation of a new anti-neoplastic therapy. The censoring date was the date of the last PS assessment prior to the cut-off or start of new therapy.	Up to approximately 18 months
Number of Participants With Dose Interruptions and Dose Reductions	The number of participants with dose reductions/interruptions was assessed and summarized by study treatment.	From randomization until end of treatment, assessed up to approximately 18 months
Dose Intensity for Alpelisib and Olaparib	Dose intensity was computed as the ratio of actual cumulative dose received to actual duration of exposure and summarized by study treatment.	From randomization until end of treatment, assessed up to approximately 18 months
Dose Intensity for Paclitaxel	Dose intensity was computed as the ratio of actual cumulative dose received to actual duration of exposure and summarized by study treatment.	From randomization until end of treatment, assessed up to approximately 18 months
Dose Intensity for Pegylated Liposomal Doxorubicin	Dose intensity was computed as the ratio of actual cumulative dose received to actual duration of exposure and summarized by study treatment.	From randomization until end of treatment, assessed up to approximately 18 months
Area Under the Curve Calculated to the End of a Dosing Interval (Tau) at Steady-state (AUCtau) of Alpelisib and Olaparib	The AUCtau will be assessed to characterize the pharmacokinetics of alpelisib when administered in combination of olaparib	Day 8 Cycle 1 (pre-dose, 1, 2, 3, 4, 6, 8 and 24 hours post dose), Day 1 on Cycle 2, 4 and 8 (pre-dose)
Area Under the Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast)of Alpelisib and Olaparib	The AUClast will be assessed to characterize the pharmacokinetics of alpelisib when administered in combination of olaparib	Day 8 Cycle 1 (pre-dose, 1, 2, 3, 4, 6, 8 and 24 hours post dose), Day 1 on Cycle 2, 4 and 8 (pre-dose)
Maximum Concentration (Cmax) of Alpelisib and Olaparib	The Cmax will be assessed to characterize the pharmacokinetics of alpelisib when administered in combination of olaparib	Day 8 Cycle 1 (pre-dose, 1, 2, 3, 4, 6, 8 and 24 hours post dose), Day 1 on Cycle 2, 4 and 8 (pre-dose)
Time to Reach Maximum Concentration (Tmax) of Alpelisib and Olaparib	The Tmax will be assessed to characterize the pharmacokinetics of alpelisib when administered in combination of olaparib	Day 8 Cycle 1 (pre-dose, 1, 2, 3, 4, 6, 8 and 24 hours post dose), Day 1 on Cycle 2, 4 and 8 (pre-dose)
Time to Definitive Deterioration by 10% in FACT-O Trial Outcomes Index (TOI) Score	The Functional Assessment of Cancer Therapy-Ovarian (FACT O) is a validated instrument that evaluates quality of life in patients with ovarian cancer. The Trial Outcome Index (TOI) of the FACT-O combines Physical Well Being (PWB), Functional Well Being (FWB), and the Ovarian Cancer Subscale (OCS), and its scores range from 0 to 100, with higher scores indicating better quality of life and physical/functional status. Time to definitive deterioration by 10% in FACT O TOI is defined as the time from randomization to the first occurrence of at least a 10% worsening from baseline with no subsequent improvement above this threshold, or death. Participants without an event before analysis cut off or before starting another anticancer therapy were censored at their last adequate assessment. Time to deterioration was estimated using the Kaplan-Meier method.	Baseline, up to 15 months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Konstantinopoulos PA, Gonzalez-Martin A, Cruz FM, Friedlander M, Glasspool R, Lorusso D, Marth C, Monk BJ, Kim JW, Hinson P, Ajipa O, Pretre V, Han Y, Matulonis UA. EPIK-O/ENGOT-OV61: alpelisib plus olaparib vs cytotoxic chemotherapy in high-grade serous ovarian cancer (phase III study). Future Oncol. 2022 Oct;18(31):3481-3492. doi: 10.2217/fon-2022-0666. Epub 2022 Sep 6.

Study record dates

Study Major Dates

• Study Start (Actual): July 22, 2021
• Primary Completion (Actual): April 21, 2023
• Study Completion (Actual): January 19, 2026

Study Registration Dates

• First Submitted: January 25, 2021
• First Submitted That Met QC Criteria: January 25, 2021
• First Posted (Actual): January 28, 2021

Study Record Updates

• Last Update Posted (Actual): June 4, 2026
• Last Update Submitted That Met QC Criteria: June 3, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: olaparib; paclitaxel; pegylated liposomal doxorubicin; Alpelisib; high grade; serous ovarian; fallopian or peritoneal cancer; no germline BRCA mutation; BRCA wild type; platinum-resistant or refractory; prior PARP inhibitor exposure; EPIK-O
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Endocrine System Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Genital Diseases, Female; Endocrine Gland Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Neoplasms, Female; Gonadal Disorders; Ovarian Neoplasms; Organic Chemicals; Hydrocarbons; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Taxoids; Cyclodecanes; Diterpenes; Paclitaxel; liposomal doxorubicin; olaparib; Alpelisib
• Other Study ID Numbers: CBYL719K12301; 2024-510782-42-00 (Registry Identifier: EU CT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No