BACKGROUND: Progression-free survival (PFS) is a crucial endpoint in cancer drug research. Clinician-confirmed cancer progression, namely real-world PFS (rwPFS) in unstructured text (ie, clinical notes), serves as a reasonable surrogate for real-world indicators in ascertaining progression endpoints. Response evaluation criteria in solid tumors (RECIST) is traditionally used in clinical trials using serial imaging evaluations but is impractical when working with real-world data. Manual abstraction of clinical progression from unstructured notes remains the gold standard. However, this process is a resource-intensive, time-consuming process. Natural language processing (NLP), a subdomain of machine learning, has shown promise in accelerating the extraction of tumor progression from real-world data in recent years. OBJECTIVES: We aim to configure a pretrained, general-purpose health care NLP framework to transform free-text clinical notes and radiology reports into structured progression events for studying rwPFS on metastatic breast cancer (mBC) cohorts. METHODS: This study developed and validated a novel semiautomated workflow to estimate rwPFS in patients with mBC using deidentified electronic health record data from the Nference nSights platform. The developed workflow was validated in a cohort of 316 patients with hormone receptor-positive, human epidermal growth factor receptor-2 (HER-2) 2-negative mBC, who were started on palbociclib and letrozole combination therapy between January 2015 and December 2021. Ground-truth datasets were curated to evaluate the workflow's performance at both the sentence and patient levels. NLP-captured progression or a change in therapy line were considered outcome events, while death, loss to follow-up, and end of the study period were considered censoring events for rwPFS computation. Peak reduction and cumulative decline in Patient Health Questionnaire-8 (PHQ-8) scores were analyzed in the progressed and nonprogressed patient subgroups. RESULTS: The configured clinical NLP engine achieved a sentence-level progression capture accuracy of 98.2%. At the patient level, initial progression was captured within ±30 days with 88% accuracy. The median rwPFS for the study cohort (N=316) was 20 (95% CI 18-25) months. In a validation subset (n=100), rwPFS determined by manual curation was 25 (95% CI 15-35) months, closely aligning with the computational workflow's 22 (95% CI 15-35) months. A subanalysis revealed rwPFS estimates of 30 (95% CI 24-39) months from radiology reports and 23 (95% CI 19-28) months from clinical notes, highlighting the importance of integrating multiple note sources. External validation also demonstrated high accuracy (92.5% sentence level; 90.2% patient level). Sensitivity analysis revealed stable rwPFS estimates across varying levels of missing source data and event definitions. Peak reduction in PHQ-8 scores during the study period highlighted significant associations between patient-reported outcomes and disease progression. CONCLUSIONS: This workflow enables rapid and reliable determination of rwPFS in patients with mBC receiving combination therapy. Further validation across more diverse external datasets and other cancer types is needed to ensure broader applicability and generalizability.