Allosteric inhibitors targeting PIK3CA are emerging as a promising strategy to improve the treatment of breast cancer, offering enhanced safety and tolerability compared to existing orthosteric inhibitors. These new agents, including STX-478 and RLY-2608, are under evaluation in early-phase trials and have demonstrated encouraging results in patients with PI3Kα-mutated breast cancer.
The Promise of Allosteric Inhibition
Conventional PI3Kα inhibitors, such as alpelisib, have shown efficacy in treating estrogen receptor (ER)-positive breast cancer. However, their clinical use is often limited by significant toxicities, including hyperglycemia, rash, and diarrhea, due to their action on both mutant and wild-type PI3Kα. Allosteric inhibitors, on the other hand, bind to a different site on the PI3Kα protein, allowing for more selective targeting of the mutant enzyme. This approach aims to minimize off-target effects and improve the safety profile.
Felipe Batalini, MD, a medical oncologist and assistant professor of oncology at Mayo Clinic, noted that allosteric inhibition allows for a more focused, selective targeting of the mutant type of PIK3CA, offering a better safety and tolerability profile.
Clinical Trial Data
Data from a phase 1/2 study (NCT05768139) of STX-478, an allosteric, central nervous system–penetrant, mutant-selective PI3Kα inhibitor, showed a disease control rate of 67% in patients with advanced solid tumors and PIK3CA helical and kinase domain mutations who had received prior standard-of-care therapy (n = 43). Notably, no grade 3 or higher PI3Kα wild-type toxicities were observed, and no patients discontinued STX-478 due to adverse effects.
Additional findings from the ReDiscover trial (NCT05216432) revealed that treatment with the allosteric inhibitor RLY-2608 led to an objective response rate (ORR) of 33% among all patients with PI3Kα-mutated, hormone receptor–positive, HER2-negative metastatic breast cancer (n = 52). The ORR among those with kinase mutations who received the panmutant and isoform-selective PI3Kα inhibitor was 53%.
Addressing Resistance and Expanding Treatment Options
Research has also indicated that allosteric inhibition may be effective in patients who have developed resistance to orthosteric PI3K inhibitors. Studies have shown that tumors can develop mutations in the PIK3CA gene itself or in downstream genes like AKT1 or upstream at PTEN, highlighting the pathway's critical role in tumor survival. Allosteric inhibitors have demonstrated the potential to overcome this resistance.
Furthermore, ongoing studies are exploring the use of PI3K inhibitors in combination with other therapies across various breast cancer subtypes. For example, inavolisib is being investigated with trastuzumab and pertuzumab in HER2-positive breast cancer, while alpelisib is being studied with trastuzumab and pertuzumab, as well as with chemotherapy (nab-paclitaxel) in triple-negative breast cancer.
The Future Landscape
The development of allosteric PIK3CA inhibitors represents a significant advancement in the treatment of breast cancer. By selectively targeting mutant PI3Kα and minimizing off-target effects, these agents offer the potential for improved efficacy and reduced toxicity. As these inhibitors advance through clinical trials, they may provide valuable new options for patients with PI3Kα-mutated breast cancer, including those who have failed prior therapies.
