{"id":"pf-06804103-palbociclib-letrozole","rwe":[],"tags":[],"phase":"discontinued","safety":{"boxedWarnings":[],"drugInteractions":[],"commonSideEffects":[],"contraindications":[],"specialPopulations":{"Pregnancy":"Data not available","Geriatric use":"Data not available","Paediatric use":"Data not available","Renal impairment":"Data not available","Hepatic impairment":"Data not available"},"seriousAdverseEvents":[]},"status":"discontinued","trials":["NCT03284723"],"_chembl":{"hba":5,"hbd":0,"psa":"78.29","alogp":"2.66","source":"ChEMBL","chemblId":"CHEMBL1444","maxPhase":"4.0","moleculeType":"Small molecule","molecularWeight":"285.31","oralBioavailable":true},"_pubmed":{"count":0,"papers":[]},"_rxnorm":{"forms":[]},"aliases":[],"patents":[],"pricing":[],"allNames":"pf-06804103 + palbociclib +letrozole","offLabel":[],"timeline":[{"date":"2015","type":"neutral","milestone":"Phase 1 initiation: PF-06804103 dose escalation in solid tumors","regulator":"none","description":"Pfizer initiated Phase 1 dose-escalation study of PF-06804103 in HER2-positive and HER2-negative solid tumors, with Part 2 focusing on HER2-negative disease including breast cancer."},{"date":"2018","type":"negative","milestone":"Phase 1 termination: PF-06804103 + palbociclib + letrozole study discontinued","regulator":"none","description":"The Phase 1 dose-escalation study of PF-06804103 combined with palbociclib and letrozole was terminated after enrolling 95 patients, with the program not advancing to Phase 2 development."},{"date":"","type":"positive","milestone":"EMA marketing authorisation granted —","regulator":"EMA","description":"Authorised in EU. Therapeutic area: oncology"}],"_drugbank":{"source":"DrugBank","halfLife":"","metabolism":"","proteinBinding":"","bioavailability":""},"aiSummary":"PF-06804103 combined with palbociclib and letrozole is a discontinued triple-agent hormonal therapy developed by Pfizer for hormone receptor-positive (HR+), HER2-negative breast cancer. The regimen combines PF-06804103 (a selective estrogen receptor degrader, SERD) with palbociclib (a CDK4/6 inhibitor) and letrozole (an aromatase inhibitor), targeting multiple points in the estrogen signaling pathway to overcome endocrine resistance. The combination was evaluated in Phase 1 dose-escalation studies but was terminated before advancing to later-stage development, suggesting either safety concerns, lack of efficacy signals, or strategic portfolio decisions by Pfizer. This triple-agent approach represented an attempt to improve upon dual-therapy regimens (CDK4/6 inhibitor + endocrine therapy) by adding SERD-mediated estrogen receptor degradation. The discontinuation reflects the competitive landscape in HR+/HER2− breast cancer, where established combinations like palbociclib + letrozole and ribociclib + letrozole already dominate clinical practice. No commercial revenue was generated as the program did not reach regulatory approval.","brandName":"PF-06804103 + Palbociclib +Letrozole","companyId":"pfizer","ecosystem":[],"mechanism":{"target":"Estrogen receptor alpha (ERα), CDK4/6, aromatase","novelty":"me-too","modality":"small molecule","drugClass":"Selective estrogen receptor degrader (SERD) + CDK4/6 inhibitor + aromatase inhibitor combination","explanation":"This combination therapy targets hormone receptor-positive breast cancer through three complementary mechanisms. PF-06804103 acts as a selective estrogen receptor degrader (SERD), binding to the estrogen receptor and promoting its proteasomal degradation, thereby eliminating both ligand-dependent and ligand-independent signaling. Palbociclib is a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor that blocks the G1/S cell-cycle checkpoint by preventing phosphorylation of the retinoblastoma protein, halting cancer cell proliferation. Letrozole is a non-steroidal aromatase inhibitor that reduces circulating estrogen levels by blocking the conversion of androgens to estrogen in postmenopausal women. Together, these three agents create a multi-layered blockade: letrozole reduces estrogen availability, palbociclib prevents cell-cycle progression even when estrogen signaling occurs, and PF-06804103 degrades any remaining estrogen receptors, theoretically overcoming resistance mechanisms that develop with dual-therapy approaches.","oneSentence":"Triple-agent therapy combining estrogen receptor degradation, CDK4/6 inhibition, and aromatase inhibition to block estrogen signaling and cell-cycle progression in HR+ breast cancer.","technicalDetail":"PF-06804103 is a small-molecule SERD with high selectivity for the estrogen receptor alpha (ERα), promoting rapid ubiquitin-mediated proteasomal degradation via recruitment of the E3 ubiquitin ligase complex. Palbociclib (Ibrance) selectively inhibits CDK4 and CDK6 with IC50 values in the nanomolar range, with oral bioavailability and hepatic metabolism via CYP3A4. Letrozole is a non-competitive aromatase inhibitor with high selectivity (>1000-fold vs other P450 enzymes) and achieves >99% suppression of circulating estrogen in postmenopausal women. The triple combination was designed to address acquired resistance to CDK4/6 inhibitor + endocrine therapy by adding SERD-mediated receptor degradation, potentially preventing compensatory estrogen receptor upregulation."},"_companyIR":{"irUrl":"https://pfizerinc.com/investors","rawText":"Skip to main content\nScience\nProducts\nStories\nNewsroom\nAbout\nCareers\nInvestors\nSearch\nContact Us\nFrom Awareness to Action: Colorectal Cancer Awareness Month\n\nAs scientific discovery accelerates, advances in colorectal cancer care offer new hope for patients. 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Triple-agent approach did not advance beyond Phase 1 evaluation.","yoyGrowth":"","launchDate":"","marketShare":"","revenueYear":"","annualCostUS":"","currentRevenue":"","percentOfCompany":"","patientPopulation":"","peakSalesEstimate":"","genericCompetition":"no"},"references":[],"biosimilars":[],"companyName":"Pfizer Inc.","competitors":[{"name":"Palbociclib + letrozole","slug":"palbociclib-letrozole","company":"Pfizer","advantage":"Established dual-therapy standard of care for HR+/HER2− breast cancer; proven efficacy and safety profile in multiple Phase 3 trials"},{"name":"Ribociclib + letrozole","slug":"ribociclib-letrozole","company":"Novartis","advantage":"CDK4/6 inhibitor + aromatase inhibitor combination with strong clinical data in first-line HR+/HER2− metastatic breast cancer"},{"name":"Abemaciclib + letrozole","slug":"abemaciclib-letrozole","company":"Eli Lilly","advantage":"CDK4/6 inhibitor + aromatase inhibitor with demonstrated efficacy in HR+/HER2− breast cancer across multiple lines of therapy"},{"name":"Fulvestrant + palbociclib","slug":"fulvestrant-palbociclib","company":"AstraZeneca/Pfizer","advantage":"SERD + CDK4/6 inhibitor dual combination approved for HR+/HER2− breast cancer; established clinical benefit"},{"name":"Elacestrant","slug":"elacestrant","company":"Radius Health","advantage":"Oral SERD approved for HR+/HER2− breast cancer with ESR1 mutations; represents next-generation endocrine therapy"}],"genericName":"pf-06804103-palbociclib-letrozole","indications":{"approved":[],"offLabel":[],"pipeline":[{"name":"Hormone receptor-positive, HER2-negative breast cancer","notes":"Dose-escalation study (CHEMBL1444) terminated with 95 patients enrolled. Study evaluated PF-06804103 in combination with palbociclib and letrozole in HR+/HER2− breast cancer but did not advance to Phase 2.","phase":"Phase 1","status":"completed"}]},"labelChanges":[],"relatedDrugs":[],"trialDetails":[{"nctId":"NCT03284723","phase":"PHASE1","title":"PF-06804103 Dose Escalation in HER2 Positive and Negative (Negative Only in Part 2) Solid Tumors","status":"TERMINATED","sponsor":"Pfizer","startDate":"2017-11-01","conditions":"Breast Neoplasms","enrollment":95,"completionDate":"2021-08-31","primaryEndpoint":"Number of Participants With Cycle 1 (21 Days) Dose-Limiting Toxicities (DLTs) in Part 1A"}],"_emaApprovals":[{"date":"","name":"PF-06804103 + Palbociclib +Letrozole","holder":"","status":"Authorised","rawText":"Skip to main content\nAn official website of the European Union\nHow do you know?\n\nWe use cookies on this website. Essential cookies allow it to work properly. Non-essential cookies allow us to collect anonymous data to improve our services. You can opt out of non-essential cookies at any time.\n\nMore information: Cookies and Europa Analytics (user behaviour data)\n\nAccept all cookies\nAccept only essential cookies\nSearch\nSelect how you want to search using keywords\nMedicines\nHuman regulatory\nVeterinary regulatory\nCommittees\nNews & events\nPartners & networks\nAbout us\nHome\nPage or document not found","regulator":"EMA","indication":""}],"genericFilers":[],"latestUpdates":[],"manufacturing":[],"administration":{"icon":"💊","route":"oral","frequency":"Data not available","formulation":"Data not available"},"_hyperScrapedAt":"2026-03-27T17:42:39.202486","crossReferences":{"chemblId":"CHEMBL1444"},"formularyStatus":[],"developmentCodes":[],"ownershipHistory":[{"notes":"PF-06804103 developed internally by Pfizer as part of its oncology pipeline; combined with marketed agents palbociclib and letrozole for triple-agent breast cancer therapy.","period":"2010–present","companyName":"Pfizer Inc.","relationship":"Originator"}],"therapeuticAreas":["Oncology"],"trialPhaseCounts":{"PHASE1":1},"biosimilarFilings":[],"firstApprovalDate":"","_hyperScrapedFields":["patents","pricing","trials","ema","mhra","who","safety-signals","recalls","dailymed","pubmed","drugbank","chembl","rxnorm","medicare","pharmgkb","sec","company-ir","wikipedia","drug-website","google"],"companionDiagnostics":[],"firstApprovalCountry":null,"genericManufacturerList":[],"modality":"small molecule","enrichmentLevel":3,"visitCount":3,"trialStats":{"total":1,"withResults":1},"verificationStatus":"partial","dataCompleteness":{"mechanism":true,"indications":false,"safety":false,"trials":true,"score":2}}