MK-2400 Phase 1 will start recruiting soon

[Maxone73]

The investigational TROP2-directed ADC, MK-2400, has shown significant promise with a notable 52.4% objective response rate in challenging non-small cell lung cancer trials.

TROP2 is also a relevant target expressed in advanced prostate cancer, so a Phase 1 clinical trial for metastatic castration-resistant prostate cancer (mCRPC) is set to begin enrollment soon.

I hope the efficacy will be on par with NSCLC!

prostatewarriors.com/2025/0...

[PCaWarrior]

Synergy Between TROP2-Targeted ADCs and Propionate Bipolar Androgen Therapy (pBAT)

TROP2-targeted ADCs (e.g., MK-2400, sacituzumab govitecan) have strong mechanistic potential to synergize with pBAT in prostate cancer. Below is the evidence and rationale:

Mechanistic Rationale for Synergy

1. DNA Damage Overload

• pBAT (SPT phase): Induces DNA double-strand breaks (DSBs) via AR-mediated replication stress and oxidative damage [PMC6763228].

• TROP2 ADCs: Deliver topoisomerase I inhibitors (e.g., SN-38, DXd) that cause lethal DNA damage by trapping PARP-DNA complexes and blocking repair.

• Combined Effect: Overwhelm DNA repair mechanisms (e.g., BRCA1/2, ATM), leading to synthetic lethality.

2. TROP2 Upregulation in pBAT

• AR Signaling Drives TROP2:

• AR binds the TACSTD2 promoter/enhancer, upregulating TROP2 expression in AR-driven tumors [PMC10261916].

• pBAT’s SPT phase may amplify TROP2 expression, enhancing ADC targeting.

• Precedent: AR-V7+ tumors show higher TROP2 levels, suggesting pBAT’s AR activation could increase ADC efficacy [ASCO GU 2025].

3. Immune Activation

• pBAT: Triggers immunogenic cell death and PD-L1 upregulation, priming tumors for checkpoint inhibitors (e.g., nivolumab) [COMBAT trial, NCT03554317].

• TROP2 ADCs: Induce immunogenic cell death, releasing tumor antigens that synergize with pBAT’s immune effects.

4. Overcoming Resistance

• pBAT Resensitizes to AR-Targeted Therapies: Alternating SPT/ADT reverses AR downregulation, a common resistance mechanism [PMC9711876].

• TROP2 ADCs Target Heterogeneous Clones: Effective against AR-low/neuroendocrine subtypes that evade BAT [PMC8012837].

Preclinical and Clinical Support

Evidence Type Findings

TROP2 Expression High in 90% of mCRPC, including ARSI-resistant tumors [PMC10261916].

BAT + PARPi Synergy BAT + olaparib showed 50% PSA50 responses in mCRPC (NCT03516812).

ADC + Androgen Synergy Sacituzumab govitecan + enzalutamide improved PFS in breast cancer models.

pBAT + PARPi + TROP2-Targeted ADC