Praful Ravi

The prevalence, clinical impact, and clonal dynamics of clonal hematopoiesis (CH) in patients receiving ¹⁷⁷Lu-PSMA-617 (LuPSMA) for metastatic castration-resistant prostate cancer (mCRPC) are unknown. Methods: Targeted next-generation sequencing of 21 genes recurrently mutated in CH was performed on DNA extracted from the peripheral blood of patients who received at least 4 cycles of LuPSMA for mCRPC at our institution between 2022 and 2023. Pathogenic somatic mutations with a variant allele fraction of at least 1% were identified using a standardized pipeline. Clinical outcomes pertaining to efficacy (overall survival [OS], measured from date of planned cycle 5) and hematologic toxicity of LuPSMA were collected from the electronic medical record. Results: Fifty patients treated with LuPSMA were eligible, with a median follow-up of 23 mo. At least 1 CH variant was detected in 33 patients (66%). The most common mutations were TET2 (n = 16), PPM1D (n = 15), and DNMT3A (n = 6). OS was similar in patients with or without CH (12-mo OS, 92% vs. 80%; hazard ratio, 0.89; 95% CI, 0.3-2.68). There was a trend toward greater hematologic toxicity in patients with CH, with a greater need for growth factor support (12% vs. 0%). In patients with serial samples available, the emergence of new clones or expansion of preexisting CH variants was detected in most patients, particularly with PPM1D and TP53-mutant clones. The key limitation was the small sample size and short follow-up. Conclusion: CH was highly prevalent and tended to lead to greater hematologic toxicity in patients with mCRPC receiving LuPSMA. Expansion or emergence of DNA damage repair CH clones was very common during and after LuPSMA therapy. Further study of the impact of CH on radiopharmaceutical therapy, particularly when used in earlier prostate cancer disease settings, is warranted.

Background: Prostate cancer (PC) arising in patients with low testosterone is often more aggressive and less responsive to androgen deprivation therapy (ADT). This study evaluated whether baseline testosterone group (low vs. normal) modifies the mortality benefit of adding docetaxel to radiation therapy (RT) and ADT in nonmetastatic high‐risk PC. Methods: From two randomized trials of docetaxel plus RT and ADT versus RT and ADT for T1c‐4N0M0 PC, 255 patients with minimal or no comorbidity comprised the discovery cohort (median age, 65 years; follow‐up, 10.4 years) and 563 patients with Eastern Cooperative Oncology Group performance status 0/1 formed the validation cohort (median age, 66 years; follow‐up, 10.6 years). Multivariable Cox regression with an interaction between treatment arm and testosterone group (normal or low level) was used to evaluate all‐cause mortality (ACM) risk by adjusting for age, T category, Gleason score, prostate‐specific antigen (PSA) level, percent positive biopsy cores, and performance status. Results: Randomization to RT, ADT, and docetaxel was associated with a significant reduction in ACM risk among patients with normal but not low testosterone, with a significant treatment‐by‐testosterone group interaction in both the discovery ( p = .048) and validation cohorts ( p = .042). Among patients with normal testosterone, those most likely to benefit from docetaxel had a PSA level of >20 ng/mL, T3/4 disease, or a Gleason score of 9/10 in both cohorts. Conclusions: Low testosterone at diagnosis does not appear to predict a reduced mortality risk when adding docetaxel to RT and ADT in otherwise healthy patients with nonmetastatic high‐risk PC, whereas normal testosterone does, which provides evidence to support testosterone group as a predictive biomarker.

PURPOSE: 177Lu-PSMA-617 (LuPSMA) is an approved prostate-specific membrane antigen (PSMA)–targeted radiopharmaceutical therapy for men with metastatic castration-resistant prostate cancer (mCRPC). Older patients, particularly octogenarians, represent a substantial proportion of men with mCRPC but have been traditionally underrepresented in key registrational trials of LuPSMA. METHODS: This retrospective multi-institutional study evaluated patients age 80 years and older with mCRPC after chemotherapy treated with ≥1 cycle of LuPSMA from August 2022 to December 2024. Clinical and demographic data were abstracted from electronic medical records. Outcomes included prostate specific antigen (PSA) response (PSA50 and PSA90), progression-free survival (PFS), overall survival (OS), and toxicities. Kaplan-Meier methods estimated PFS/OS; descriptive statistics summarized baseline and safety data. RESULTS: Ninety-five patients (median age, 83 years) were included, of whom 36 (38%) and 21 (22%) had a history of cardiac disease or chronic kidney disease, respectively. Median follow-up was 24.1 months (IQR, 6.7-28.1). Patients received a median of five cycles of LuPSMA. Fifty-two (57%) and 21 (23%) patients achieved a PSA50 and PSA90, respectively. Median PFS and OS were 7.3 months (95% CI, 6.4 to 8.7) and 13.5 months (95% CI, 9.7 to 18.8), respectively. Grade ≥3 hematologic toxicities included anemia (n = 19; 20%) and thrombocytopenia (n = 4, 4%); grade ≥3 acute kidney injury occurred in one patient. Fourteen (15%) patients had dose delays, seven (7%) required reductions, and 10 (11%) discontinued therapy due to toxicity. Thirty-seven patients (39%) were hospitalized during therapy, with intensive care unit-level care required in two patients (2%), and there was one treatment-related death. CONCLUSION: LuPSMA had comparable outcomes in octogenarians with mCRPC to patients on registrational trials, although 2/5 of patients required hospitalization during therapy. These findings support the feasibility and efficacy of LuPSMA in well-selected older men with mCRPC and suggest a role for closer monitoring of older patients.

Supplementary Figure S3. Kaplan–Meier curves for (A) overall survival (OS) and (B)progression-free survival (PFS) stratified by treatment group (immune checkpoint inhibitor (IO), tyrosine kinase inhibitor (TKI), and IO + TKI). Median survival times with 95% confidence intervals (CI) and log-rank p-values are shown within each panel. Number-at-risk tables are displayed below the curves.

Supplementary Figure S1. Cohort Flow Diagram Flowchart summarizing the distribution of the 33 patients by disease stage at presentation and subsequent treatment. Sixteen patients were metastatic at diagnosis, and ten additional patients developed metastases during follow-up. Among metastatic cases, 23 received systemic therapy (Biphasic Hyalinizing Psammomatous [BHP] n = 13; non-BHP n = 10), while 3 received no systemic treatment (all BHP). Locoregional patients who did not develop metastases were treated with BHP (n = 6) or non-BHP (n = 1). Dashed arrows indicate progression to metastatic disease.

Purpose:In renal cell carcinoma (RCC), loss of the NF2 tumor suppressor gene encoding the merlin protein is associated with aggressive clinical behavior. However, data about the clinical course and additional molecular features in the context of contemporary systemic therapies remain limited.Experimental Design:Clinical outcomes were evaluated in patients with RCC exhibiting merlin loss by IHC in one academic cohort. Integrative genomic analyses were performed, including targeted DNA sequencing via the institutional OncoPanel assay and RNA sequencing data from The Cancer Genome Atlas (TCGA).Results:In the institutional cohort (n = 33), most patients had biphasic hyalinizing psammomatous RCC (66.6%) and metastatic disease (78.8%). Among 23 patients receiving systemic therapy, those treated with non-immunotherapy (IO)–based regimens (n = 5) had numerically longer overall survival (24.5 vs. 16.5 months, P = 0.2) and progression-free survival (9.8 vs. 5 months, P = 0.5) compared with IO-based therapies (n = 18) though differences were not statistically significant. Genomic analysis (n = 17) revealed frequent truncating mutations of NF2 (82.3%) and recurrent alterations in chromatin remodeling and DNA damage–response signaling genes with prominent deletions in tumor suppressor genes such as CDKN2A/B. Transcriptomic profiling of NF2-inactivated tumors from TCGA (n = 13) demonstrated enrichment of cellular proliferation and concurrent suppression of metabolic and immune pathways, suggesting an aggressive phenotype compared with clear-cell RCC without NF2 inactivation (n = 529).Conclusions:Biallelic NF2 inactivation and merlin protein deficiency drive an aggressive RCC phenotype marked by immune dysfunction, high proliferation, and frequent cell cycle and DNA damage–response signaling alterations. Limited treatment response to IO highlights the need for molecularly tailored therapies.

Supplementary Figure S2. Systemic Therapy Sequences Across Treatment Lines This Sankey diagram illustrates the distribution and transitions of systemic therapies across treatment lines in the cohort. The first column represents treatments received in the first-line setting, followed by subsequent columns showing second-, third-, fourth-, and fifth-line therapies. Each colored flow corresponds to a specific drug or drug combination, with stream widths proportional to the number of patients receiving that regimen. The diagram highlights the heterogeneity of treatment patterns, sequencing, and the diversity of regimens used over the course of therapy.

Supplementary Figure S4. The Cancer Genome Atlas (TCGA) Mutation Landscape in NF2-Altered Renal Cell Carcinoma