Phase 1/2 Trial: Targeting Resistance With SX-682 And Apalutamide Or Enzalutamide
Scientists are exploring a novel combination therapy involving SX-682 and Apalutamide or Enzalutamide to combat metastatic castration-resistant prostate cancer (mCRPC). This innovative approach aims to overcome the limitations of current treatments by targeting cancer from two distinct angles.
SX-682 acts as a dual antagonist of CXCR1 and CXCR2, two chemokine receptors that play a crucial role in the tumor’s microenvironment. Tumors often create an “immunosuppressive cloak” by recruiting myeloid cells, such as myeloid-derived suppressor cells (MDSCs) and neutrophils, which shield the cancer from the body’s immune system . By blocking CXCR1/2, SX-682 inactivates these immunosuppressive myeloid cells, effectively “heating up” the immunologically “cold” prostate cancer environment and allowing the body’s own T cells and natural killer cells to more effectively attack the cancer . This mechanism also helps reverse chemo-resistance and block metastasis .
The synergy between SX-682 and Apalutamide / Enzalutamide lies in their complementary actions. Apalutamide and Enzalutamide directly attacks the cancer cells by disrupting their hormonal signaling, while SX-682 works to dismantle the protective, immunosuppressive environment that often allows cancer to resist therapies thee ARSi. This dual-pronged approach is hypothesized to not only enhance the initial effectiveness of treatment but also to delay or prevent the emergence of resistance, thereby offering a more durable response for patients. Preclinical studies have shown that high levels of CXCR2 ligands are negatively prognostic for overall survival in mCRPC patients, highlighting the importance of targeting this pathway. SX-682 has also demonstrated its ability to synergize with other anti-cancer agents by favorably modulating the tumor microenvironment.
By combining a potent androgen receptor inhibitor with an agent that re-educates the tumor microenvironment, researchers hope to provide a new, more effective strategy for these patients.
A Phase 1/2 clinical trial, known as ASpiRE (NCT07002320), is currently recruiting participants to evaluate the safety, tolerability, and anti-tumor activity of Apalutamide with SX-682 in men with mCRPC.
Another Phase 1/2 trial, known as SYNERGY-201 (NCT06228053), is instead recruiting participants to evaluate the combination of SX-682 and Enzalutamide.