Prostate cancer lung metastasis represents a clinical conundrum due to its implications for advanced disease progression and the complexities it introduces in treatment planning. As the disease progresses to distant sites such as the lung, the clinical management becomes increasingly intricate, requiring tailored therapeutic strategies to address the unique characteristics of metastatic lesions. This review seeks to synthesize the current state of knowledge surrounding prostate cancer metastasis to the lung, shedding light on the diverse array of clinical presentations encountered, ranging from subtle radiological findings to overt symptomatic manifestations. By examining the diagnostic modalities utilized in identifying this metastasis, including advanced imaging techniques and histopathological analyses, this review aims to provide insights into the diagnostic landscape and the challenges associated with accurately characterizing lung metastatic lesions in prostate cancer patients. Moreover, this review delves into the nuances of therapeutic interventions employed in managing prostate cancer lung metastasis, encompassing systemic treatments such as hormonal therapies and chemotherapy, as well as metastasis-directed therapies including surgery and radiotherapy.

It is well known that patients with liver metastasis from metastatic castration-resistant prostate cancer have poor or only transient responses to many forms of systemic therapy. Data on outcomes after treatment with [¹⁷⁷Lu]Lu-PSMA-617 (LuPSMA) are scarce. The VISION trial reports a hazard ratio for overall survival (OS) in the subgroup of patients with liver metastasis without disclosing the absolute duration of survival. Using real-world clinical data, we examined this important subgroup of patients, describing prostate-specific antigen (PSA) response and OS. Methods: A single-institution database was assembled to include all patients receiving LuPSMA at Mayo Clinic in Rochester, Minnesota, for whom treatment was initiated between March 2022 and March 2023. Baseline clinicopathologic and imaging characteristics were abstracted. Patients were then categorized by presence or absence of liver metastasis on pretreatment prostate-specific membrane antigen (PSMA) PET. PSA response and OS for the 2 groups (liver metastasis vs. no liver metastasis) were compared using χ² testing and the Kaplan–Meier method, respectively. A multivariate Cox regression analysis was performed, including established prognostic factors. Finally, those with pretreatment circulating tumor DNA as determined in an 83-gene panel were assessed for the presence of pathogenic and likely pathogenic alterations. These findings were summarized using descriptive statistics and compared between the 2 cohorts using the Fisher exact test. Results: The overall cohort consisted of 273 patients, including 43 (15.75%) with liver metastasis on pretreatment PSMA PET/CT. The median number of cycles received was 3 (range, 1–6) for patients with liver metastasis and 5 (range, 1–6) for those without hepatic involvement. The 50% or greater reduction in PSA from baseline response rate was lower for those with liver metastasis than for those without (30.23% [13/43] vs 49.77% [106/213], P = 0.019). At a median follow-up of 10 mo (interquartile range, 9–13 mo), there was a significant difference in median OS (8.35 mo vs. not reached, P < 0.001). On multivariate analysis, the presence of liver metastasis was independently associated with shorter survival (hazard ratio, 4.06; P < 0.001). Conclusion: Our data suggest that the presence of liver metastasis predicts poorer outcomes in patients receiving LuPSMA treatment. Alternative and combination approaches should be explored to maximize the antitumor activity of radiopharmaceutical therapy in the liver. Visual Abstract

Background: Longitudinal genomic profiling through serial circulating tumor DNA (ctDNA) testing offers a noninvasive method to monitor clonal evolution in advanced prostate cancer. This study evaluated the frequency and nature of newly emergent and potentially actionable genomic alterations detected through serial testing in a real-world setting. Methods: We conducted a retrospective analysis of advanced prostate cancer patients who underwent multiple Guardant360 ctDNA tests between October 2020 and March 2023. The study focused on identifying new genomic alterations absent in the initial test, with particular attention to alterations relevant for on-label therapies, therapies approved in other oncologic indications (i.e., off-label), or a clinical trial. Results: Among 479 patients with at least two ctDNA tests, the median interval between the first and second evaluable tests was 207 days. New and potentially actionable alterations emerged in 57.8% of patients, including potential targets for on-label therapies (16.7%), off-label therapies (16.5%), and clinical trials (55.7%). Tumor mutational burden (TMB) increased from “low” to “high” in 11% of patients, although none had microsatellite instability or mismatch repair deficiency. In a Mayo Clinic subset, ten patients received olaparib based on treatment-emergent alterations, but none achieved a prostate-specific antigen (PSA) response. Two patients who transitioned from low to high TMB received pembrolizumab, both with progressive disease as best response. Conclusions: In a large real-world cohort, serial ctDNA testing frequently identified new alterations that were not detected at baseline and are potentially actionable therapeutic targets, highlighting the value of serial genomic profiling for capturing clonal dynamics. Additional research is needed to better establish a framework for retesting and to clarify how these results should influence subsequent treatment decisions.