Background: In preclinical studies, the oncolytic reovirus pelareorep promoted an inflammatory tumor microenvironment (TME) by promoting greater infiltration of tumor infiltrating lymphocytes and upregulating PD-1/PD-L1 expression, potentially increasing the efficacy of immune checkpoint blockade. The addition of pelareorep to paclitaxel (PTX) was associated with improved survival (10.4 vs. 17.4 mos., HR = 0.65, p = 0.1) in a prior trial, with the greatest benefit in patients (pts) with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) disease (N = 57; 10.8 vs. 21.0 mos., HR 0.60, p = 0.1). Methods: This is a randomized phase 2 study in pts with HR+/HER2- metastatic breast cancer. Patients must have progressed on at least one hormone therapy with a CDK4/6 inhibitor. After a safety run-in for Cohort 3, patients were randomized 1:1:1 to PTX-alone (Cohort 1), PTX + pelareorep (Cohort 2), or PTX + pelareorep + avelumab (Cohort 3). The primary endpoint was overall response rate (ORR) at week 16 according to RECIST v1.1 without formal comparison across groups. Toxicity, progression-free survival (PFS) and overall survival were secondary endpoints. Blood samples were collected at cycle 1-day 1 (C1D1), C2D1 and C4D1, and T-cell receptor sequencing was performed. Results: Forty-eight pts were enrolled between June 2020 and June 2022. Median age was 55.5 yrs, range 37-74. Forty pts (83%) had visceral disease. Six pts (12%) previously received everolimus, and 3 alpelisib. Thirteen pts (27%) received prior taxanes in the neo/adjuvant setting. Three pts who withdrew consent prior to starting therapy and 2 pts who discontinued treatment after week 1 were considered non-responders and were censored for PFS. The most common pelareorep-associated toxicities were fever, chills, and flu-like infusion reactions, which were occasionally severe enough to require hospitalization in 5 (15%) pts despite acetaminophen prophylaxis. Nine pts (33%) discontinued pelareorep and 6 (35%) discontinued avelumab due to toxicity. Pelareorep increased T-cell repertoire turnover, with identification and expansion of new and pre-existing T-cell clones by C2D1. Conclusions: The addition of pelareorep to PTX is an active regimen with a high 6-month PFS rate worthy of further study. One third of patients discontinued either pelareorep or avelumab due to toxicity, highlighting the need for attentive supportive care. Survival data is maturing. Clinical trial information: NCT04215146.