Transformation to squamous cell carcinoma (SCC) after initial treatment of a primary prostate adenocarcinoma is rare and typically results in rapid treatment-refractory disease progression and death. Here, we present a case of a 70-year-old man who was initially treated with prostatectomy and radiotherapy, and later developed bone metastases. After commencing systemic therapy with androgen deprivation therapy (ADT) and apalutamide, his prostate-specific antigen (PSA) declined to undetectable levels, yet short-interval imaging demonstrated oligo-progression at T4, with biopsy specimen demonstrating pure SCC. Molecular profiling of both the primary prostate tumor and T4 demonstrated alterations in TMPRSS2-ERG, TP53, and FOXA1 confirming site of origin, with loss of RNF43 in the squamous metastasis. He was treated with stereotactic body radiation therapy to the SCC metastasis and continued on ADT and apalutamide with stable disease for a year post-radiation. This case highlights the importance of imaging to detect non–PSA-producing metastatic disease, the utility of radiation therapy in oligo-progression, and use of molecular profiling to provide insights into the pathogenesis of histologic transformation.

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Author notes

Source of support: Sidney Kimmel Center for Prostate and Urologic Cancers at Memorial Sloan Kettering Cancer Center (MSK) and the National Institutes of Health/National Cancer Institute Cancer Center Support Grant to MSK (P30 CA008748).

Competing Interests

Conflict of Interest: Karen Autio reports trial support funding to the institution from Pfizer, AstraZeneca, Amgen, Trishula Therapeutics, Eli Lilly, and the Parker Institute for Cancer Immunotherapy. Sean McBride reports trial support funding to the institution from AstraZeneca, Janssen, and Roche.

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