Study Design: This is a placebo-controlled, randomized phase III clinical trial.

Background: There is an unmet need for effective treatment for patients with hormone receptor positive and human epidermal growth factor negative advanced/metastatic breast cancer that have progressed on two lines of endocrine-based therapy. Novel agents being investigated in this setting pose significant financial toxicity with disease control ranging from 7 to 13 months in the 2nd or 3rd line of therapy. Combination chemotherapy with hormone therapy could address the intra-tumoral heterogeneity post multiple lines of therapy. Megestrol acetate has demonstrated response rates of 30 percentage and median progression-free survival of 3 months in heavily pre-treated patients with MBC, irrespective of estrogen and/or progesterone receptor status. In a non-randomized trial, the addition of chemotherapy to MA in 29 heavily pretreated MBC patients reported a median PFS of 7 months and no significant toxicities. Hence, we hypothesize that combination of MA with chemotherapy will improve PFS in patients with HR+ MBC. In this study, we are testing this hypothesis by comparing two arms: MA plus capecitabine vs capecitabine plus placebo.

Aim:To evaluate the efficacy and safety of combination capecitabine and megestrol acetate in patients with HR positive  MBC who are chemotherapy naïve.

Primary Objective: To compare progression-free survival between patients receiving capecitabine with megesterol acetate versus capecitabine with placebo which is Identical to MA 

Secondary Objective: To compare the 2 groups for: Overall Survival between both arms, objective response rates in patients with measurable disease ,Clinical Benefit Rate, Safety , Quality of Life

Key Inclusion Criteria: Age 18 and above years ,post-menopausal women or pre-menopausal women on ovarian suppression, Histologically proven breast cancer:  In advanced or metastatic stage HR positive either estrogen receptor positive and/or progesterone receptor positive as per ASCO-CAP guidelines HER2 negative defined as IHC 2 positive/ISH negative or IHC 0 and 1 positive. Received at least two lines of endocrine-based therapy for advanced or metastatic disease or had cancer progression while undergoing adjuvant endocrine therapy or within 12 months of completion of adjuvant endocrine therapy. Prior CDK4 or 6 inhibitor is mandatory.  Have received no prior line of chemotherapy in the metastatic setting. ECOG PS less than 2.

Key Exclusion Criteria: Contraindication to capecitabine. Patients with prior megestrol acetate or current exposure to natural/synthetic progesterone compounds.Patients with uncontrolled brain metastases. Patients with a history of venous thromboembolism or known thrombophilia

Treatment Plan: Consenting patients will be randomly assigned to Arm A Experimental Group : Megestrol acetate (MA) 160 mg per oral once a day with capecitabine 1000 mg per m2 PO BD for 2 weeks with 1 week off in every 3 weekly cycles Arm B Control Group: Placebo which is identical in appearance with Megestrol acetate with capecitabine 1000 mg per m2 PO BD for 2 weeks with 1 week off in every 3 weekly cycles Treatment will continue until disease progression, intolerable toxicity or patient decision to stop.

Follow-up assessments: Patients will be followed up for clinical assessment and laboratory parameters every 21 window period of pluse or minus 3 days. Assessment of disease status with contrast-enhanced computed tomography of the thorax, abdomen, and pelvis will be performed every 12 window period of pluse or minus 1 weeks. After disease progression, subsequent treatment administration will be as per standard institutional practice, and patients will be followed up every 3 months until death.

Statistical Consideration: This is randomised, placebo-controlled, phase III trial in which 332 patients with MBC will be randomized with equal probability to one of two possible treatment regimens: MA 160 mg per oral once a day with capecitabine 1000 mg per m2 PO BD for 2 weeks with 1 week off in every 3 weekly cycles or Placebo (identical in appearance to MA) administered per oral once a day and capecitabine 1000 mg per m2 PO BD for 2 weeks with 1 week off in every 3 weekly cycles. With 329 PFS events, the log-rank test has a power of 0.90 to detect a hazard ratio of 0.70  an increasing the median PFS from 6 months to 8 months with a two-sided type I error rate of 0.05. The following calculations assume a monthly accrual rate of 9 patients or month accrued over a 39 month period, followed for 24 months after study closure and that PFS is assumed to follow an exponential distribution.