a study to evaluate the efficacy and safety of giredestrant in combination with phesgo (pertuzumab, trastuzumab, and hyaluronidase-zzxf) versus phesgo in participants with locally advanced or metastatic breast cancer (heredera breast cancer)

Conditions: Locally Advanced or Metastatic Breast Cancer

Summary: this phase iii, randomized, two-arm, open-label, multicenter study will evaluate the efficacy and safety of giredestrant plus phesgo compared with phesgo after induction therapy with phesgo plus taxane in participants with human epidermal growth factor receptor 2 (her2)-positive, estrogen receptor (er)-positive advanced breast cancer (metastatic or locally advanced disease not amenable to curative treatment) who have not previously received a systemic non-hormonal anti-cancer therapy in the advanced setting.


Eligibility criteria:
inclusion criteria: * histologically or cytologically confirmed and documented human epidermal growth factor receptor 2 (her2)-positive/estrogen receptor (er)-positive adenocarcinoma of the breast with metastatic or locally-advanced disease not amenable to curative resection * at least one measurable lesion and/or non-measurable disease evaluable according to response evaluation criteria in solid tumors (recist) version 1.1 * disease-free interval from completion of adjuvant or neoadjuvant systemic non-hormonal treatment to recurrence of ≥6 months * eastern cooperative oncology group (ecog) performance status 0 or 1 * left ventricular ejection fraction (lvef) of at least (≥)50% measured by echocardiogram (echo) or multiple-gated acquisition scan (muga) * adequate hematologic and end-organ function * for women of childbearing potential: participants who agree to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agree to refrain from donating eggs, during the treatment period and for 7 months after the final dose of phesgo * for men: participants who agree to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agree to refrain from donating sperm, during the treatment period and for 7 months after the final dose of phesgo to avoid exposing the embryo maintenance phase inclusion criteria * complete a minimum of four cycles to a maximum of eight cycles of induction therapy; the minimum cycles are defined as either: phesgo injections + 4 docetaxel infusions, or phesgo injections + 12 paclitaxel infusions * achieve a minimum of stable disease (sd) (or non-complete response \[cr\]/non-progressive disease \[pd\] for participants with non-measurable disease) (i.e., did not experience pd) according to recist v1.1 at the last tumor assessment during the induction therapy phase * lvef of ≥50% at the last assessment during the induction therapy phase exclusion criteria: * previous systemic non-hormonal anti-cancer therapy in the metastatic breast cancer (mbc) or advanced breast cancer (abc) setting. note: up to one line of single-agent endocrine therapy given in the metastatic or locally advanced setting will be allowed. * prior treatment with a selective estrogen receptor degrader (serd) * previous treatment with approved or investigative anti-her2 agents in any breast cancer treatment setting, except phesgo (or trastuzumab sc with pertuzumab iv, or pertuzumab and trastuzumab iv), single-agent trastuzumab iv or sc, ado-trastuzumab emtansine, lapatinib, and neratinib in the neoadjuvant or adjuvant setting * disease progression within 6 months of receiving adjuvant anti-her2 therapy (such as trastuzumab, with or without pertuzumab \[iv, sc, or fixed-dose combination\], or ado-trastuzumab emtansine, or neratinib) * non-resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to national cancer institute common terminology criteria for adverse events version 5.0 (nci ctcae v5.0) grade 1 or better * history of persistent grade ≥2 (nci-ctc, version 5.0) hematological toxicity resulting from previous adjuvant or neo-adjuvant therapy * history of exposure to the following cumulative doses of anthracyclines; doxorubicin \>360 mg/m2; liposomal doxorubicin \>500 mg/m2; epirubucin \>720 mg/m2; mitoxantrone \>120 mg/m2; idarubicin \>90 mg/m2. * known active uncontrolled or symptomatic central nervous system (cns) metastases, carcinomatous meningitis, or leptomeningeal disease * dyspnea at rest due to complications of advanced malignancy, or other disease requiring continuous oxygen therapy * pregnant or breastfeeding, or intending to become pregnant during the study or within 7 months after the final dose of phesgo (women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of induction therapy). * treated with investigational therapy within 28 days prior to initiation of induction therapy * treated with localized palliative radiotherapy within 14 days prior to initiation of induction therapy * concurrent participation in any other therapeutic clinical trial * known hypersensitivity to any of the study medications or to excipients of recombinant human or humanized antibodies * current chronic daily treatment (continuous for \>3 months) with corticosteroids (dose of 10 mg/day methylprednisolone or equivalent) * poorly controlled hypertension * known clinically significant history of liver disease consistent with child-pugh class b or c, active liver disease including active viral or other hepatitis virus, autoimmune hepatic disorders, or sclerosing cholangitis, current alcohol abuse, or cirrhosis * active cardiac disease or history of cardiac dysfunction * major surgical procedure or significant traumatic injury within 14 days prior to enrollment or anticipation of need for major surgery during induction therapy * active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or major upper gastrointestinal surgery * concurrent, serious, uncontrolled infections, or known infection with hiv with the following exception: individuals who are hiv positive are eligible provided they are stable on anti-retroviral therapy for ≥4 weeks, have a cd4 count ≥350 cells/ul, and have an undetectable viral load and no history of aids-defining opportunistic infections within 12 months prior to enrollment. * serious covid-19 infection within 14 days prior to enrollment; however, no screening testing for sars-cov-2 is required * serious infection requiring oral or iv antibiotics within 7 days prior to screening * any serious medical condition or abnormality in clinical laboratory tests that precludes an individual's safe participation in the study * history of malignancy within 5 years prior to screening with the exception of the cancer under investigation in this study and malignancies with a negligible risk of metastasis or death * for pre- and perimenopausal women, and men: known hypersensitivity to luteinizing hormone-releasing hormone agonist (lhrha); not willing to undergo and maintain treatment with approved lhrha therapy for the duration of endocrine therapy that requires gonadal function suppression * treatment with strong cyp3a4 inhibitors or inducers within 14 days or 5 drug-elimination half-lives, whichever is longer, prior to initiation of giredestrant treatment in arm b * a documented history of hemorrhagic diathesis, coagulopathy, or thromboembolism, including deep vein thrombosis, unless the condition is adequately treated and under control