Wise, David R

TPS276 Background: Metastatic castration-resistant prostate cancer (mCRPC) can evolve into a neuroendocrine-like subtype with aggressive behavior and poor outcomes (1). Nuclear Receptor-Binding SET Domain Protein 2 (NSD2) is overexpressed in prostate cancer and is a driver of both androgen-receptor (AR)-dependent signaling and of neuroendocrine differentiation, where cancer cells lose AR dependence and response to AR pathway inhibitors (ARPIs) (2,3,4). In studies of patient-derived neuroendocrine prostate cancer (NEPC) models, genetic depletion of NSD2 led to restoration of AR expression, reversal of adeno-to-neuroendocrine differentiation, and re-sensitization to ARPI (4). We hypothesize that NSD2 inhibition can reverse resistance to ARPIs in patients with progressive mCRPC, including with neuroendocrine differentiation. KTX-2001 is an oral, potent and selective small molecule inhibitor of NSD2. It is the sponsor’s second NSD2 inhibitor to enter the clinic. The sponsor’s first in class NSD2 inhibitor, KTX-1001, was shown to be tolerable and have preliminary efficacy in patients with relapsed/refractory multiple myeloma (5). Methods: STRIKE-001 (NCT07103018) is a multicenter, open-label phase 1 dose escalation trial of KTX-2001 monotherapy (Part A) and KTX-2001 + darolutamide (Part B). Key inclusion criteria are males age ≥18 years with mCRPC, progression after receiving ARPI, Eastern Cooperative Oncology Group performance score of 0-1, willingness to undergo biopsy if safe and feasible, and life expectancy of ≥6 months. Participants take KTX-2001 by mouth once daily alone (Part A) or with darolutamide 600 mg twice daily (Part B). Dose escalation of KTX-2001 in Parts A and B will follow a 3+3 design and occur in parallel at multiple planned dose levels. Primary objectives are to assess the safety and tolerability, determine MTD, and determine RP2D(s) for further study of KTX-2001 alone and in combination with darolutamide. Secondary objectives include characterization of efficacy and PK parameters for both KTX-2001 monotherapy and in combination with darolutamide. Exploratory objectives include study of pharmacodynamic effects, circulating tumor cells, and cell-free DNA. 1. Conteduca V, Eur J Cancer 2019. 2. Parolia A, Nat Genet 2024. 3. Aytes A, Nat Commun 2018 4. Li J, bioRxiv 2023.07.18.549585 5. Bories P, Blood Vol 144, Suppl 1,2024. Clinical trial information: NCT07103018 .

TPS5130 Background: Patients with prostate cancer and deleterious HRRa have poorer prognosis but derive benefit from poly (ADP-ribose) polymerase (PARP) inhibition. However, prevalence of HRRa and response to PARP inhibition are less well defined in racial/ethnic minorities. We designed the HARMONY trial to evaluate the efficacy of N/AA/P in HL and NHB patients with mHSPC and deleterious HRRa. Methods: This multicenter, open label, phase II study is open through the Hoosier Cancer Research Network in the United States. The trial enrolls patients who self-identify as HL or NHB and have mHSPC with HRRa including BRCA 1/2, BRIP1, CHEK2, FANCA, PALB2, RAD51B, and/or RAD54L. Eligible patients will have hormone sensitive, treatment naïve or minimally treated prostate cancer (i.e., bicalutamide ≤ 45 days, androgen deprivation therapy [ADT] ± AA plus P ≤ 45 days allowed). Prostate cancer variants, other therapy in mHSPC setting, or symptomatic brain metastases are exclusionary. Enrolled patients will receive 24 weeks (w) of ADT plus N/AA dual action tablet (DAT) plus P, followed by an adaptive approach based on prostate specific antigen (PSA) response. Subjects in Arm A (PSA > 4.0 ng/mL at 24 w) can continue ADT/N/AA/P for max 2 years or stop N and escalate therapy to ADT/AA/P plus 6 cycles of docetaxel followed by standard of care (SOC) therapy. Subjects in Arm B (PSA ≤ 4.0 ng/mL at 24 w) will continue ADT/N/AA/P for a total of 12 months. At 12 months in Arm B, subjects with PSA ≥ 0.2 ng/mL will continue ADT/N/AA/P for max 2 years, and subjects achieving PSA < 0.2 ng/mL have the option to continue ADT/N/AA/P for max 2 years or discontinue all therapy with the option to start SOC treatment at disease progression. PSA decline to < 0.2 ng/mL at 24w (primary endpoint) will be evaluated for each racial/ethnicity group against a historic rate of 50%. Thirty patients per racial/ethnic cohort will give 80% power at 0.1 significance to determine noninferiority with a no-inferiority margin of 0.185. Estimating 5% drop out, 64 patients will be enrolled (n=32 HL and n=32 NHB). Key secondary/exploratory endpoints include PSA reduction ≥ 90%, overall response rate, PSA/radiographic progression free survival, overall survival, time to subsequent anti-cancer therapy, quality of life and safety. Key genomic correlatives will be evaluated. ClinicalTrials.gov: NCT06392841. Study support of drug and funding: Janssen Scientific Affairs LLC. Clinical trial information: NCT06392841 .

Indications for and implications of germline genetic testing (GGT) in patients with prostate cancer have expanded over the past decade, particularly related to precision therapies and management. GGT has become the standard of care for many cancers such as breast, ovarian, colorectal, pancreatic, and metastatic prostate cancer, and it is imperative that patients be offered timely and equitable access to testing as it can inform patient-physician shared decision making for management of the current cancer as well as anticipatory guidance for disease progression. Additionally, GGT guides screening for and prevention of secondary malignancies for the patient and cascade testing for at-risk family members. Here, we present data supporting the notion that clinicians should offer all patients with prostate cancer the opportunity to undergo comprehensive GGT for pathogenic germline variants known to be associated with familial cancer and/or known to have implications for treatment and management.