Fatima Karzai

Objectives: To determine the relationship between gynaecomastia and testosterone levels in patients with biochemically recurrent prostate cancer treated with androgen receptor pathway inhibitor (ARPI) monotherapy. Patients and Methods: This analysis evaluates changes in serum testosterone and the incidence of gynaecomastia. Patients with biochemically recurrent prostate cancer were given 3 months of enzalutamide intermittently with no androgen deprivation. Serum testosterone was within the normal range. Testosterone and adverse events were monitored prospectively. Results: A total of 38 patients were enrolled with a median age of 64.6 years, median (range) serum prostate‐specific antigen level of 4.38 (2.01–19.43) ng/mL, and median (range) serum testosterone level of 316 (167–723) ng/dL. Testosterone had a median peak of 832.5 ng/dL (median increase of 63%). Gynaecomastia symptoms were reported in 16 (42%) patients. There was no correlation with either peak testosterone level or duration of elevated testosterone and gynaecomastia. Patients with gynaecomastia with Course 1 of therapy did not fully predict the incidence of gynaecomastia for Course 2. Conclusions: In this study, there is no direct correlation between ARPI monotherapy‐associated testosterone elevation and the incidence of gynaecomastia. The interactions of ARPI monotherapy, gynaecomastia, and testosterone elevation are more nuanced than previously thought and require further study to optimise ARPI monotherapy in clinical practice.

Background: Immune checkpoint blockade is minimally active in unselected castration-resistant prostate cancer (CRPC) and does not reproducibly yield durable decreases in prostate-specific antigen (PSA) levels. Methods: The Quick Efficacy Seeking Trial was designed to employ a combination of agents to initiate an immune response (with BN-Brachyury vaccine), potentiate that response (with nogapendekin-alfa inbakicept (NAI), an interleukin (IL)-15 receptor superagonist), and reduce or eliminate immunosuppressive entities in the tumor microenvironment (with bintrafusp alfa, a dual inhibitor of programmed death-ligand 1 and transforming growth factor beta). Epacadostat (an indoleamine 2,3-dioxygenase (IDO) inhibitor) was also employed in one cohort to reduce immune suppression induced by IDO’s conversion of tryptophan to kynurenine. Results: Patients with CRPC enrolled sequentially to receive vaccine + bintrafusp alfa (Arm 2.1), vaccine + bintrafusp alfa + NAI (Arm 2.2), and vaccine + bintrafusp alfa + NAI + epacadostat (Arm 2.3), with the primary objective to determine response rate. Adverse events in Arms 2.1 and 2.2 were manageable and consistent with the safety profiles of each agent individually, and notable for five individuals developing isolated adrenocorticotropic hormone deficiency. Arm 2.3 was closed early due to skin toxicity. Sustained declines in PSA were seen in 1/13 (8%) patients in Arm 2.1, 7/24 (29%) patients in Arm 2.2, including six with proficient mismatch repair/microsatellite stable tumors, and 0/6 (0%) patients in Arm 2.3. Conclusions: Analyses of peripheral immune profiles provided evidence of a multifaceted antitumor immune response, including IL-15 receptor superagonist NAI-dependent expansion and activation of natural killer cells and CD8 ⁺ T cells, increased effector-to-suppressor immune cell ratios, and induction of cytotoxic immune gene programs. Trial registration number: NCT03493945 .

Background: Metastatic castration-resistant prostate cancer (mCRPC) remains an aggressive disease with limited response to systemic therapies despite androgen deprivation. Immune-excluded prostate tumors are typically resistant to immunotherapy. STAR0602 is a selective bifunctional T-cell agonist composed of an antibody targeting Vβ6 and Vβ10 T-cell receptor chains fused to human interleukin-2 that selectively expands Vβ6 ⁺ CD8 ⁺ memory T cells and has demonstrated clinical activity as a monotherapy in anti-programmed death-ligand 1-resistant tumors ( NCT05592626 ). We hypothesized that combining poly ADP-ribose polymerase (PARP) inhibition with Vβ-directed T-cell activation would enhance antitumor immunity and promote polyclonal T-cell responses in immune-excluded prostate cancer. Methods: The antitumor activity of the PARP inhibitor olaparib combined with mSTAR1302, the murine surrogate of STAR0602, was evaluated in TRAMP-C2 and RM-1 prostate tumor models. Tumor growth, survival, and immune responses were assessed by flow cytometry and functional depletion studies. The role of tumor-intrinsic TRAIL-R2 signaling was evaluated using a TRAIL-R2 knockout TRAMP-C2 model, and clinical relevance was explored by assessing TRAIL-R2 expression in tumor samples from patients treated with olaparib in a Phase 2 clinical trial ( NCT02484404 ). Results: Combination therapy with olaparib and mSTAR1302 induced significant tumor regression and improved survival compared with either agent alone. Treatment increased tumor-infiltrating lymphocytes, expanded activated Vβ13 ⁺ CD4 ⁺ and Vβ13 ⁺ CD8 ⁺ T cells, reduced immunosuppressive populations, and enriched stem-like progenitor exhausted CD8 ⁺ T cells. Depletion studies demonstrated that Vβ13 ⁺ CD4 ⁺ T cells, Vβ13 ⁺ CD8 ⁺ T cells, natural killer cells, and interferon-γ were required for therapeutic efficacy. TRAIL-R2 knockout experiments demonstrated that tumor-intrinsic TRAIL-R2 signaling contributes to the antitumor activity of the combination. Mechanistically, these findings support a model in which PARP inhibition sensitizes tumors while mSTAR1302-mediated Vβ13 ⁺ T-cell expansion initiates a broader polyclonal antitumor immune response associated with antigen spreading and recognition of multiple tumor antigens and neoepitopes. Conclusions: These findings suggest that combining tumor-sensitizing therapies with selective T-cell activation may represent a broader strategy to overcome immune exclusion in solid tumors. Together, these results provide mechanistic rationale for clinical evaluation of olaparib in combination with STAR0602 in patients with mCRPC who have progressed on androgen deprivation therapy.

MECOM Overexpression CRPC are vulnerable to PARP inhibitors and inhibitors of the DNA repair pathway irrespective of HRR or DDR genes mutation status

MECOM suppression enhances spheroid inhibition and apoptosis

Ranking of Differential Expressed Transcription Factors Related to Figure 1C

PARP inhibitors in combination with enzalutamide suppress MECOM and AR expression, suppress proliferation, and increase apoptosis in enzalutamide-resistant CRPC

MECOM overexpression is associated with treatment resistance

Functional suppression of MECOM alters AR binding and H3K27ac enrichment in CRPC cell lines