The androgen receptor (AR) transduces the effects of circulating and tumor-derived androgens to the nucleus through ligand-induced changes in protein conformation, localization, and chromatin engagement. Defining how these events are integrated with signal transduction is critical to understand how AR drives prostate cancer and unveil pathway features that are potentially amenable to therapeutic intervention. We describe a novel post-transcriptional mechanism that controls AR levels on chromatin and gene output based on highly selective, inducible degradation. We find that the mono-ADP-ribosyltransferase PARP7 generates an ADP-ribosyl degron in the DNA-binding domain of AR, which is recognized by the ADP-ribose reader domain in the ubiquitin E3 ligase DTX2 and degraded by the proteasome. Mathematical modeling of the pathway suggested that PARP7 ADP-ribosylates chromatin-bound AR, a prediction that was validated in cells using an AR DNA-binding mutant. Non-conventional ubiquitin conjugation to ADP-ribosyl-cysteine and degradation by the proteasome forms the basis of a negative feedback loop that regulates modules of AR target genes. Our data expand the repertoire of mono-ADP-ribosyltransferases to include gene regulation via highly selective protein degradation.

Androgen-indifferent prostate cancer (AIPC) is increasingly common and particularly lethal. Data describing these tumors are sparse, and AIPC remains a poorly understood malignancy. Utilizing the Oncology Research Information Exchange Network (ORIEN) database, we enriched for tumors with features of AIPC using previously described characteristics. Our AIPC cohort included three subgroups: aggressive variant prostate cancer (AVPC), neuroendocrine PC (NEPC), and double-negative PC (DNPC). Of 1496 total PC patients available for analysis, we identified 323 (22%) as MCRPC. Of those, 39 (12%) met AIPC criteria (17 AVPC, 13 NEPC, 9 DNPC) and 284 (88%) were non-AIPC. Forty-three percent of AIPC patients had de novo metastatic disease vs. 15% for non-AIPC (p = 0.003). Homologous recombination deficiency (HRD) and tumor mutational burden (TMB) did not differ between cohorts, but microsatellite instability scores (MSI) were significantly higher in AIPC (p = 0.019). Using Gene Set Enrichment Analysis (GSEA), we found that genes defining response to androgens and genes involved in oxidative phosphorylation were the most downregulated, whereas genes involved in epithelial–mesenchymal transition (EMT) and immune signaling were significantly upregulated in AIPC vs. non-AIPC. Our study demonstrates the potential for predefined criteria that aim to enrich for AIPC and suggests opportunities for therapeutic investigation.

Background: Despite the therapeutic advances made in castration-sensitive prostate cancer, progression to castration-resistant disease is inevitable. Lutetium-177 vipivotide tetraxetan (¹⁷⁷Lu-PSMA-617) is a novel radioligand approved for use in metastatic castration-resistant prostate cancer (mCRPC). With promising efficacy, it is not without numerous potential side effects, namely cytopenias, which are often a reason for early discontinuation of ¹⁷⁷Lu-PSMA-617. We sought to describe the incidence of cytopenias associated with permanent discontinuation of ¹⁷⁷Lu-PSMA-617 at our institution. Methods: We conducted a retrospective review of patients who received ¹⁷⁷Lu-PSMA-617at the University of Virginia Comprehensive Cancer Center from 2018 to 2025. From this we assessed for the incidence of toxicities resulting in permanent discontinuation of ¹⁷⁷Lu-PSMA-617, which we refer to as dose-limiting toxicities. Descriptive statistics were used to summarize characteristics of the study population. Median overall survival from time of initiation of ¹⁷⁷Lu-PSMA-617 was estimated using a Kaplan–Meier curve. Results: Of the patients who received ¹⁷⁷Lu-PSMA-617 (n = 64), grade 3 or greater anemia occurred in 36% (n = 23), thrombocytopenia in 3% (n = 2), leukopenia in 3% (n = 2), neutropenia in 0% (n = 0), and lymphopenia in 33% (n = 21). In our cohort, 10.9% (n = 7) developed toxicities necessitating permanent discontinuation. Of these, 9.3% (n = 6) were attributable to cytopenias. Those cytopenias consisted of anemias in 100% (n = 6) of cases, leukopenia in 83% (n = 5), thrombocytopenia in 67% (n = 4), lymphopenia in 100% (n = 6), and neutropenia in 33% (n = 2). Aside from cytopenias, the remaining 1.6% (n = 1) of dose-limiting toxicities were attributable to renal injury. In the VISION trial, the ¹⁷⁷Lu-PSMA-617 treatment arm reported dose-limiting toxicities necessitating permanent discontinuation in 11.9% of participants, but did not report if these were attributable to cytopenia or other toxicities. Notably, 2 patients developed grade 5 pancytopenia and 1 patient developed grade 5 bone marrow failure in the VISION ¹⁷⁷Lu-PSMA-617 treatment arm. Compared to the VISION ¹⁷⁷Lu-PSMA-617 treatment arm, our cohort differed in the distribution of organ metastases, younger median age of patients, and a higher portion of those with ECOG 2 functional status. From the time of ¹⁷⁷Lu-PSMA-617 initiation, median overall survival was estimated to be 18.5 months, compared to 15.3 months in the VISION ¹⁷⁷Lu-PSMA-617 treatment arm. Conclusions: In our real-world analysis, 85% of dose-limiting toxicities necessitating ¹⁷⁷Lu-PSMA-617 discontinuation were attributed to cytopenias. Though a direct comparison cannot be made with the VISION ¹⁷⁷Lu-PSMA-617 treatment arm in terms of dose-limiting toxicity attributable specifically to cytopenias, they reported total dose-limiting toxicity to a similar degree, and cytopenias were the most common causes of grade 3 or greater toxicities. Therefore, it is important to recognize the ubiquity of these adverse events as well as the role that they play in therapy-limiting toxicity.