In March 2026, Ipsen voluntarily withdrew the EZH2 inhibitor tazemetostat (Tazverik) from all markets and indications following results from the confirmatory Phase Ib/III SYMPHONY-1 trial demonstrating hematologic second primary malignancies (SPMs) in 5.7% of treated patients, compared with none in the control arm. The most frequently reported SPMs were myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Although this finding may be interpreted as an idiosyncratic liability of a single agent, the biology of EZH2 suggests a broader, target-driven risk. EZH2 functions in a context-dependent manner as both an oncogene and a tumor suppressor. Gain-of-function mutations drive transformation in germinal center B-cell lymphomas, whereas loss-of-function alterations impair hematopoietic stem cell differentiation and are recurrent in myeloid malignancies, including MDS and AML. In selected solid tumor contexts, such as specific subtypes of medulloblastoma, EZH2 loss can likewise promote tumorigenesis. These observations raise concern that chronic pharmacologic inhibition of EZH2 may phenocopy loss-of-function states that initiate myeloid neoplasia. We argue that the withdrawal of tazemetostat exposes a fundamental vulnerability in the development of epigenetic therapies: target validation has focused on tumor-intrinsic effects while underweighting consequences in normal stem cell compartments. This issue is particularly relevant for ongoing Phase III programs in prostate cancer, where prolonged exposure may amplify latency-dependent risks. We propose changes to preclinical safety assessment, trial design, and pharmacovigilance to mitigate predictable, target-mediated toxicities.

Prostate cancer (PCa) is the second most common cancer in men. For patients with high-volume metastatic PCa (mPCa) who are fit for docetaxel, a triplet therapy regimen consisting of androgen deprivation therapy (ADT), chemotherapy, and an androgen receptor pathway inhibitor (ARPI) is recommended. Adding local radiotherapy to triplet therapy has been shown to alleviate symptoms and reduce disease progression. However, the benefit of combining triplet therapy with local surgery remains unclear and warrants further investigation in the present study.

Prostate cancer kills ≈350,000 yearly. While localized cases have 99% five-year survival, metastatic prostate cancer is hard to treat, with few options for tumors resistant to androgen deprivation. To leverage the immune system to fight prostate cancer, we developed a non-integrative lentiviral vector, namely "Lenti-PROST-02", which encodes clusters of T cell immunodominant regions of human prostatic acid phosphatase and prostate-specific antigen. Immunotherapy with Lenti-PROST-02 in a preclinical virulent prostate tumor model resulted in complete tumor eradication in vast majority of the treated animals. This antitumor effect was concomitant with induction of poly-functional CD8+ T splenocyte effectors against numerous T cell epitopes of the antigens encoded by Lenti-PROST-02, increased proportions of tumor-infiltrating CD8+ T cells with activated/differentiated/effector phenotype and a "cold-to-hot" inflammatory switch of the tumor microenvironment. Immunity induced by Lenti-PROST-02 was long-lasting and prevented tumor relapse. It was characterized by the persistence of CD44+ CD62L- CD127+ KLRG1- CD8+ memory T cells in secondary lymphoid organs, as well as an antigen-diversified memory response. Therefore, Lenti-PROST-02 therapeutic vaccine is a promising approach for prostate immuno-oncotherapy.

Prostate cancer is one of the major health concerns, with increasing incidence and persistent therapeutic resistance worldwide. Despite various available treatments (radiation therapy, chemotherapy, hormone therapy, cryotherapy, biological therapy, and high-intensity focused ultrasound), patients still show treatment-related side effects over many years. These challenges highlight the urgent need for novel and safe therapeutic strategies. In the present study, we repurposed five FDA-approved antifungal agents, namely natamycin (NM), terbinafine hydrochloride (TH), ketoconazole (KZ), miconazole (MZ), and clotrimazole (CZ), as they can modulate conserved cellular processes, including sterol metabolism and mitochondrial function, which are increasingly recognized as critical determinants of cancer cell survival. Our data demonstrated MZ as the most active compound that significantly reduced prostate cancer cell viability, clonogenic growth, invasion, and migration compared with other tested antifungal agents. Later, proteomic profiling revealed that MZ alters key regulators of cell-cycle progression and apoptotic signaling pathways. Furthermore, pathway enrichment analysis revealed prostate cancer as one of the top enriched pathways, p53 signaling, and other associated pathways. These findings were validated by microscopy, flow cytometry, and protein expression analyses, demonstrating that MZ induces morphological changes and G0/G1 cell-cycle arrest via downregulation of cyclin D3, CDK2, CDK4, and PCNA and activates p53-associated signaling changes characterized by increased p21 and p27 expression. These findings identify MZ as a mechanistically active repurposed candidate for prostate cancer and support further exploration for oncology drug repurposing strategies.

Decompensated heart failure (DHF) may occasionally conceal an underlying systemic malignancy. Persistent hematological abnormalities, particularly thrombocytopenia and markedly elevated alkaline phosphatase (ALP), extending beyond the acute phase of illness warrant systematic evaluation for bone marrow pathology or infiltrative disease, irrespective of the presenting diagnosis. A 53-year-old man with no prior comorbidities presented with DHF, bicytopenia (anemia and thrombocytopenia), and markedly elevated ALP. He developed disseminated intravascular coagulation (DIC) during hospitalization, managed with fresh frozen plasma (FFP), platelet concentrates, and cryoprecipitate, with subsequent resolution; however, thrombocytopenia and ALP elevation persisted. Bone marrow examination revealed infiltration by metastatic adenocarcinoma. Despite comprehensive evaluation including gastrointestinal endoscopies, contrast-enhanced computed tomography (CT), and 18-fluorodeoxyglucose positron emission tomography-CT (18-FDG PET-CT), the primary site remained elusive in the setting of multiple elevated tumor markers: prostate-specific antigen (PSA), carcinoembryonic antigen (CEA), and carbohydrate antigen (CA) 19-9. Immunohistochemistry of the bone marrow biopsy demonstrated positivity for cytokeratin (CK) and NKX3.1, establishing prostatic origin. Subsequent prostate biopsy confirmed left-lobe prostatic adenocarcinoma with a Gleason score of 4+3=7 (Grade Group 3), tumor comprising 70% of the biopsy core, and perineural invasion, consistent with high-risk locally advanced disease. The patient was commenced on androgen deprivation therapy (ADT). Persistent thrombocytopenia and markedly elevated ALP may represent the sole initial manifestation of occult metastatic prostate cancer, even in young patients with no urological symptoms. Immunohistochemistry, particularly NKX3.1, is indispensable in establishing prostatic origin when the primary site remains radiologically occult after comprehensive investigation.

Prostatic tuberculosis is a rare manifestation of genitourinary tuberculosis and may closely mimic clinically significant prostate cancer on multiparametric MRI, creating considerable diagnostic uncertainty. We report the case of a 46-year-old Nigerian man undergoing follow-up for latent tuberculosis infection who reported a progressive reduction in ejaculatory volume while attempting conception. He had minimal lower urinary tract symptoms (International Prostate Symptom Score: 1/35), a prostate-specific antigen level of 3.94 µg/L, and a palpable prostatic nodule on digital rectal examination. Multiparametric MRI demonstrated highly suspicious lesions involving both the peripheral and transition zones, together with pelvic lymphadenopathy, raising concern for clinically significant prostate cancer. Histopathological examination revealed extensive granulomatous inflammation with areas of necrosis, while Ziehl-Neelsen and fungal stains were negative. PCR testing performed on the biopsy tissue subsequently confirmed Mycobacterium tuberculosis complex, without evidence of isoniazid or rifampicin resistance. The patient completed anti-tuberculous therapy, with radiological resolution of the lesions and normalisation of prostate-specific antigen levels, although persistent ejaculatory dysfunction required specialist fertility assessment. This case highlights the ability of prostatic tuberculosis to fulfil radiological criteria typically associated with prostate malignancy despite minimal urinary symptoms. Recognition of this rare entity is important to avoid misdiagnosis, prevent inappropriate oncological management, and facilitate the timely initiation of anti-tuberculous treatment.

Transcription factors (TFs) are aspirational therapeutic targets, as their dysregulation drives altered cell states. Yet many disease-relevant TFs are disordered and lack canonical binding pockets, frustrating direct small-molecule inhibition. Indirectly targeting the effector molecules that modulate TF function is a promising, underexplored alternative. Here we report a strategy for capturing cancer-specific protein-protein interactions using context-dependent µMap photoproximity labeling. With an intein-based method for catalyst conjugation in biochemically intact nuclei, we capture unique c-Myc interactomes in healthy and cancerous prostate cells and mine them for druggable vulnerabilities. We identify STE20-like kinase (SLK), a cancer-specific interactor that stabilizes c-Myc, drives epithelial morphology and is essential for tumorigenesis. Mechanistically, SLK phosphorylates c-Myc at serine 329, antagonizing GSK3β-dependent phosphodegron phosphorylation. This interaction is associated with a splicing change promoting nuclear localization of the long SLK isoform. Patient data link this isoform to c-Myc target expression across tumor types; the interaction validates across diverse tissues.

PROpel (phase 3 randomized [1:1], double-blind trial: NCT03732820) met its primary endpoint, showing statistically significantly improved investigator-assessed radiographic progression-free survival (rPFS) with olaparib plus abiraterone versus placebo plus abiraterone in biomarker-unselected first-line metastatic castration-resistant prostate cancer (mCRPC; hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.54-0.81; p < 0.0001). Median overall survival (OS) was 42.1 mo with olaparib plus abiraterone, a 7.4-mo improvement versus placebo plus abiraterone. We report efficacy in patients with single homologous recombination repair gene mutations (HRRm). Before primary analysis, HRRm status was determined by aggregating tumor tissue (FoundationOne CDx) and circulating tumor DNA (FoundationOne Liquid CDx) assay results. Overall, 28.4% of patients had an HRRm, predominantly BRCA2 (7.3%), ATM (6.2%), and CDK12 (5.0%). HRs numerically favored olaparib plus abiraterone for rPFS (BRCA2, HR, 0.20; 95% CI, 0.08-0.44; ATM, HR, 0.55; 95% CI, 0.20-1.38; CDK12, HR, 0.51; 95% CI, 0.20-1.18) and OS (BRCA2, HR, 0.20; 95% CI, 0.07-0.48; ATM, HR, 0.79; 95% CI, 0.33-1.77; CDK12, HR, 0.57; 95% CI, 0.24-1.27). Other single-gene mutations were rare (<5 events in either arm), limiting interpretation. Findings support olaparib plus abiraterone as an important first-line option for patients with mCRPC. PREVIOUS PRESENTATION: Results were previously presented in part at the ASCO-GU 2024 congress, held on January 25-27, 2024: San Francisco, CA, USA.