Endocrine Therapy Plus CDK4/6 in First or Second Line for Hormone (SONIA) Receptor Positive Advanced Breast Cancer

NCT03425838 | Active Not Recruiting Phase 3 DMC

• 2 other identifiers: BOOG 2017-032017-002334-23
• Study Type: interventional
• Target: 1,050
• Locations: 1 country
• Sites: 72

Brief Summary

Given the uncertain benefit in efficacy of adding CDK 4/6 to first rather than second line endocrine treatment, the aim of this project is to evaluate whether the sequence of an aromatase inhibitor plus CDK 4/6 in first line followed by fulvestrant in second line is superior to the sequence of an aromatase inhibitor in first line followed by fulvestrant plus CDK4/6 in second line.

Conditions

Breast Neoplasm Female

Keywords

CDK 4/6 inhibitor

Outcome Measures

Primary Outcomes (1)

• PFS2

  Progression-free survival after two lines of treatment (PFS2)

  Until objective disease progression, symptomatic deterioration, or unacceptable toxicity on second line treatment, death, strategy violation, or withdrawal of consent, whichever occurs first, assessed up to 60 months

Secondary Outcomes (15)

• OS

  Date of randomization until date of death due to any cause, assessed up to 60 months

• FACT-B questionnaire

  Questionnaires will be administered at baseline and thereafter every three months, up to 60 months

• EQ-5D questionnaire

  Questionnaires will be administered at baseline and thereafter every three months, up to 60 months

• iMTA RUQ-B questionnaire

  Questionnaires will be administered at baseline and thereafter every six months, up to 60 months

• Number of participants with grade 3 or 4 treatment-related neutropenia as assessed by CTCAE v4.0

  Through study completion, assessed up to 60 months

Study Arms (2)

Strategy A CDK4/6 inhibitor in 1st line

ACTIVE COMPARATOR

Non-steroidal aromatase inhibitor (letrozole or anastrozole, at the discretion of the treating physician) plus CDK4/6 inhibitor (palbociclib, ribociclib or abemaciclib, depending on availability and physician's preference) in first line followed by fulvestrant in second line.

Drug: CDK 4/6 inhibitor; Drug: Non-Steroidal Aromatase Inhibitor; Drug: Fulvestrant

Strategy B CDK4/6 inhibitor in 2nd line

ACTIVE COMPARATOR

Non-steroidal aromatase inhibitor (letrozole or anastrozole, at the discretion of the treating physician) in first line followed by fulvestrant plus CDK4/6 inhibitor in second line (palbociclib, ribociclib or abemaciclib, depending on availability and physician's preference).

Drug: CDK 4/6 inhibitor; Drug: Non-Steroidal Aromatase Inhibitor; Drug: Fulvestrant

Interventions

CDK 4/6 inhibitor DRUG

Adding CDK 4/6 inhibitor (pabociclib, ribociclib or abemaciclib depending on availability and physician's preference) to either first line treatment (with non-steroidal aromatase inhibitors, either letrozole or anastrozole) or second line treatment (with fulvestrant) in advanced HR+/HER2-negative breast cancer

Also known as: palbociclib,Ibrance,ribociclib,Kisqali,abemaciclib,Verzenio

Strategy A CDK4/6 inhibitor in 1st line; Strategy B CDK4/6 inhibitor in 2nd line

Non-Steroidal Aromatase Inhibitor DRUG

Adding CDK 4/6 inhibitor (pabociclib, ribociclib or abemaciclib depending on availability and physician's preference) to either first line treatment (with non-steroidal aromatase inhibitors, either letrozole or anastrozole) or second line treatment (with fulvestrant) in advanced HR+/HER2-negative breast cancer

Also known as: NSAI, letrozole, Femara®, anastrozole, Arimidex®

Strategy A CDK4/6 inhibitor in 1st line; Strategy B CDK4/6 inhibitor in 2nd line

Fulvestrant DRUG

Adding CDK 4/6 inhibitor (pabociclib, ribociclib or abemaciclib depending on availability and physician's preference) to either first line treatment (with non-steroidal aromatase inhibitors, either letrozole or anastrozole) or second line treatment (with fulvestrant) in advanced HR+/HER2-negative breast cancer

Also known as: SERD, Faslodex®

Strategy A CDK4/6 inhibitor in 1st line; Strategy B CDK4/6 inhibitor in 2nd line

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult women (≥ 18 years of age) with proven diagnosis of adenocarcinoma of the breast with evidence of loco-regional recurrent or metastatic disease not amenable to resection or radiation therapy with curative intent and for whom chemotherapy is not clinically indicated.
• Documentation of histologically or cytologically confirmed diagnosis of estrogen-receptor (ER) expression \>10% and/or progesterone receptor (PR) expression \>10% breast cancer based on local laboratory results.
• Previously untreated with any systemic anti-cancer therapy for loco-regional recurrent or metastatic HR+ disease, with the exception of recently started (within 28 days of randomization) endocrine therapy.
• Women who are not post-menopausal must use LHRH agonist. Postmenopausal status is defined as:
• prior bilateral surgical oophorectomy, or
• spontaneous cessation of regular menses for at least 12 consecutive months without OAC
• in case of doubt serum estradiol \<20 umol/l and follicle stimulating hormone (FSH) levels \>15 IU/L at screening
• Measurable or evaluable disease as defined per RECIST v.1.1 (see Appendix 3) or bone-only disease. Tumor lesions previously irradiated or subjected to other locoregional therapy will only be deemed measurable if disease progression at the treated site after completion of therapy is clearly documented.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2.
• Adequate organ and marrow function defined as follows:
• ANC ≥1,000/mm3 (1.0 x 10e9 /L);
• Platelets ≥50,000/mm3 (50 x 10e9 /L);
• Estimated creatinine clearance ≥ 30 mL/min as calculated using the method standard for the institution;
• Total serum bilirubin ≤1.5 x ULN (≤3.0 x ULN if Gilbert's disease);
• AST and ALT ≤3 x ULN (≤5.0 x ULN if liver metastases present);

You may not qualify if:

• Patients with advanced, symptomatic, visceral spread, who are at risk of life-threatening complications in the short term (including patients with massive uncontrolled effusions (pleural, pericardial, peritoneal), pulmonary lymphangitis, and over 50% liver involvement).
• Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Patients with a history of CNS metastases or cord compression are eligible if they have been definitively treated with local therapy (e.g., radiotherapy, stereotactic surgery) and are clinically stable without the use of steroids for at least 4 weeks before randomization
• Prior neoadjuvant or adjuvant treatment with an aromatase inhibitor (i.e., anastrozole, letrozole or exemestane) with disease recurrence while on or within 12 months of treatment.
• Prior treatment with any CDK4/6 inhibitor.
• Patients treated within the last 7 days prior to randomization with:
• Food or drugs that are known to be CYP3A4 inhibitors (ie, amprenavir, atazanavir, boceprevir, clarithromycin, conivaptan, delavirdine, diltiazem, erythromycin, fosamprenavir, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, voriconazole, and grapefruit or grapefruit juice);
• Drugs that are known to be CYP3A4 inducers (ie, carbamazepine, felbamate, nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentin, and St. John's wort).
• Major surgery, chemotherapy, radiotherapy, any investigational agents, or other anti-cancer therapy within 2 weeks before randomization. Patients who received prior radiotherapy to ≥25% of bone marrow are not eligible independent of when it was received.
• Diagnosis of any other malignancy prior to randomization, except those that are not believed to influence the patient's prognosis and do not require any further treatment. This includes, but is not limited to adequately treated basal cell or squamous cell skin cancer and carcinoma in situ of the cervix.
• QTc \>480 msec at baseline
• Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or any upper gastrointestinal surgery including gastric resection.
• Known hypersensitivity to letrozole or anastrozole, or any of its excipients, or to any palbociclib excipients.
• Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
• Recent or active suicidal ideation or behavior.

Sponsors & Collaborators

• Borstkanker Onderzoek Groep: lead

Study Sites (72)

Jeroen Bosch Ziekenhuis

's-Hertogenbosch, Netherlands

Location

Noordwestziekenhuisgroep

Alkmaar, Netherlands

Location

ZGT

Almelo, Netherlands

Location

Flevoziekenhuis

Almere Stad, Netherlands

Location

Meander Medisch Centrum

Amersfoort, Netherlands

Location

Ziekenhuis Amstelland

Amstelveen, Netherlands

Location

Nki - Avl

Amsterdam, 1066 CX, Netherlands

Location

VUmc

Amsterdam, 1081 HV, Netherlands

Location

AMC

Amsterdam, Netherlands

Location

BovenIJ Ziekenhuis

Amsterdam, Netherlands

Location

OLVG

Amsterdam, Netherlands

Location

Gelre ziekenhuizen

Apeldoorn, Netherlands

Location

Rijnstate

Arnhem, Netherlands

Location

Wilhelmina ziekenhuis

Assen, Netherlands

Location

Rode Kruis Ziekenhuis

Beverwijk, Netherlands

Location

Alexander Monro Ziekenhuis

Bilthoven, Netherlands

Location

Maasziekenhuis Pantein

Boxmeer, Netherlands

Location

Amphia

Breda, Netherlands

Location

IJsselland

Capelle aan den IJssel, Netherlands

Location

Reinier de Graaf

Delft, Netherlands

Location

Deventer Ziekenhuis

Deventer, Netherlands

Location

Van Weel-Bethesda Ziekenhuis

Dirksland, Netherlands

Location

Slingeland Ziekenhuis

Doetinchem, Netherlands

Location

Albert Schweitzer ziekenhuis

Dordrecht, Netherlands

Location

Nij Smellinghe

Drachten, Netherlands

Location

Gelderse Vallei

Ede, Netherlands

Location

Catharina Ziekenhuis

Eindhoven, Netherlands

Location

Maxima Medisch Centrum

Eindhoven, Netherlands

Location

Treant Zorggroep

Emmen, Netherlands

Location

Medisch Spectrum Twente

Enschede, Netherlands

Location

St. Anna Ziekenhuis

Geldrop, Netherlands

Location

Admiraal de Ruyter

Goes, Netherlands

Location

Rivas Beatrixziekenhuis

Gorinchem, Netherlands

Location

Groene Hart Ziekenhuis

Gouda, Netherlands

Location

Martini Ziekenhuis

Groningen, Netherlands

Location

UMC Groningen

Groningen, Netherlands

Location

Ropcke Zweers

Hardenberg, Netherlands

Location

Sint Jansdal

Harderwijk, Netherlands

Location

Tjongerschans

Heerenveen, Netherlands

Location

Elkerliek ziekenhuis

Helmond, Netherlands

Location

Tergooi

Hilversum, Netherlands

Location

Spaarne Gasthuis

Hoofddorp, Netherlands

Location

Dijklander Ziekenhuis

Hoorn, Netherlands

Location

MC Leeuwarden

Leeuwarden, Netherlands

Location

Alrijne Ziekenhuis

Leiden, Netherlands

Location

LUMC

Leiden, Netherlands

Location

St. Antonius

Nieuwegein, Netherlands

Location

Canisius-Wilhelmina Ziekenhuis

Nijmegen, Netherlands

Location

Radboudumc

Nijmegen, Netherlands

Location

Laurentius

Roermond, Netherlands

Location

Bravis ziekenhuis

Roosendaal, Netherlands

Location

Erasmus MC

Rotterdam, 3015 CE, Netherlands

Location

Franciscus Gasthuis & Vlietland

Rotterdam, Netherlands

Location

Ikazia

Rotterdam, Netherlands

Location

Maasstad Ziekenhuis

Rotterdam, Netherlands

Location

Zuyderland

Sittard, Netherlands

Location

Antonius Ziekenhuis

Sneek, Netherlands

Location

Spijkenisse Medisch Centrum

Spijkenisse, Netherlands

Location

ZorgSaam

Terneuzen, Netherlands

Location

Haaglanden Medisch Centrum

The Hague, Netherlands

Location

HaGaziekenhuis

The Hague, Netherlands

Location

Ziekenhuis Rivierenland

Tiel, Netherlands

Location

Elisabeth Tweesteden

Tilburg, Netherlands

Location

Bernhoven

Uden, Netherlands

Location

Diakonessenhuis

Utrecht, Netherlands

Location

UMC Utrecht

Utrecht, Netherlands

Location

VieCuri

Venlo, Netherlands

Location

St. Jans Gasthuis

Weert, Netherlands

Location

Streekziekenhuis Koningin Beatrix

Winterswijk, Netherlands

Location

Zaans Medisch Centrum

Zaandam, Netherlands

Location

Langeland

Zoetermeer, Netherlands

Location

Isala

Zwolle, Netherlands

Location

Related Publications (4)

• Wortelboer N, Kent S, Blommestein HM, van Ommen-Nijhof A, van der Noort V, van den Pol E, Paez CG, Beeker A, Beelen K, Hamming LC, Heijns JB, Honkoop AH, de Jong PC, van Rossum-Schornagel QC, van de Mheen CVS, Tol J, Driel CST, Vrijaldenhoven S, van Leeuwen-Stok AE, Sonke GS, Jager A, Konings IR. Health-related quality of life with first- vs second-line CDK4/6 inhibitor use in advanced breast cancer: results from the SONIA trial. J Natl Cancer Inst. 2025 Nov 21:djaf334. doi: 10.1093/jnci/djaf334. Online ahead of print.

  PMID: 41270788 DERIVED

• Wortelboer N, Kent S, Konings IR, van Ommen-Nijhof A, van der Noort V, van den Pol E, Guerrero Paez C, van Bekkum ML, van den Berkmortel FWPJ, Droogendijk HJ, Houtsma D, Oosterkamp HM, van der Padt-Pruijsten A, Siemerink EJM, Tol J, van Zweeden AA, van Leeuwen-Stok AE, Sonke GS, Jager A, Blommestein HM. Health economic outcomes and costs of CDK4/6 inhibitor use in first- versus second-line for advanced breast cancer: A cost-effectiveness analysis of the phase 3 SONIA trial. Eur J Cancer. 2025 Dec 9;231:116051. doi: 10.1016/j.ejca.2025.116051. Epub 2025 Oct 25.

  PMID: 41207182 DERIVED

• Jongbloed EM, Wortelboer N, de Weerd V, Beaufort CM, Ruigrok-Ritstier K, Van MN, Kraan J, van Zweeden AA, van der Padt-Pruijsten A, Hamming LC, Konings IR, Sonke GS, Oomen-de Hoop E, Martens JWM, Jager A, Wilting SM. Early versus deferred use of CDK4/6 inhibitors in advanced breast cancer: circulating tumor DNA analysis of a randomized phase 3 trial. Nat Med. 2025 Nov;31(11):3662-3667. doi: 10.1038/s41591-025-03935-w. Epub 2025 Sep 4.

  PMID: 40908356 DERIVED

• van Ommen-Nijhof A, Konings IR, van Zeijl CJJ, Uyl-de Groot CA, van der Noort V, Jager A, Sonke GS; SONIA study steering committee. Selecting the optimal position of CDK4/6 inhibitors in hormone receptor-positive advanced breast cancer - the SONIA study: study protocol for a randomized controlled trial. BMC Cancer. 2018 Nov 20;18(1):1146. doi: 10.1186/s12885-018-4978-1.

  PMID: 30458732 DERIVED

MeSH Terms

Interventions

palbociclib; Letrozole; Anastrozole; Fulvestrant

Intervention Hierarchy (Ancestors)

Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• A. Jager, MD, PhD

  Borstkanker Onderzoek Groep

  PRINCIPAL INVESTIGATOR

• A E van Leeuwen-Stok, PhD

  BOOG Study Center

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 15, 2017
• First Posted: February 8, 2018
• Study Start: November 9, 2017
• Primary Completion: March 6, 2023
• Study Completion: December 1, 2025
• Last Updated: September 19, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

NL (72)