Sydney, Australia, September 1, 2026
Kazia Therapeutics has announced plans to expand its ongoing paxalisib clinical trial into hormone receptor-positive (HR+)/HER2-negative breast cancer, following new preclinical findings showing significant antitumor activity and a favorable safety profile in combination with standard-of-care therapies. The company said the data also indicate that paxalisib may help resensitize treatment-resistant tumors, including tumors that have developed resistance to CDK4/6 inhibitors. Based on these findings, Kazia is amending its ongoing triple-negative breast cancer (TNBC) clinical trial protocol to establish a new three-arm expansion for patients with pre-treated HR+/HER2- metastatic breast cancer. The first patient is expected to be enrolled before the end of 2026, with full enrollment anticipated by the end of 2027.
Paxalisib Shows Activity in HR+/HER2- Models
The new development is supported by preclinical studies evaluating paxalisib in HR+ breast cancer models. Kazia reported that paxalisib combined with fulvestrant, an endocrine therapy, and paxalisib combined with fulvestrant plus palbociclib, a CDK4/6 inhibitor, produced statistically significant reductions in tumor volume across preclinical models while maintaining consistent safety findings. In a HR+ xenograft model, the three-drug combination reduced tumor burden without additional toxicity and produced primary tumor growth inhibition comparable to gedatolisib when used with the same regimen. Kazia’s benchmarking studies further suggest that paxalisib may restore sensitivity to combination treatment through a distinct epigenetic mechanism, an effect the company says was not observed with gedatolisib. These findings are being used to support the company’s clinical strategy for addressing treatment resistance in HR+/HER2- disease. HR+/HER2- breast cancer represents a substantial portion of the breast cancer population, accounting for approximately 60–70% of breast cancer diagnoses, according to Kazia. Despite the availability of endocrine therapies, targeted agents and antibody-drug conjugates, treatment resistance remains a major challenge in advanced disease. Kazia believes paxalisib could potentially intervene at a deeper biological level by targeting the PI3K/mTOR–epigenetic resistance axis, rather than relying solely on conventional pathway inhibition. The company has also filed a provisional patent application covering aspects of the approach and identified a novel PI3K/mTOR-related biomarker that may help identify a high-risk subset of metastatic HR+/HER2- patients.
Three-Arm Clinical Expansion Targets Treatment Resistance
Under the planned clinical expansion, patients with pre-treated HR+/HER2- metastatic breast cancer will be randomized into three treatment groups. One arm will receive paxalisib 15 mg plus fulvestrant and palbociclib, while a second arm will receive paxalisib 30 mg plus fulvestrant and palbociclib. The third arm will serve as a standard-of-care comparator, consisting of fulvestrant. The primary endpoint will assess safety and tolerability, while secondary endpoints will include progression-free survival (PFS), overall response rate (ORR), and overall survival (OS). Kazia expects clinical updates throughout 2027, with a full data readout anticipated in 2028. The trial expansion adds another clinical development path for paxalisib, an investigational, brain-penetrant inhibitor of the PI3K/Akt/mTOR pathway. Kazia is evaluating the molecule across multiple cancer settings, including advanced breast cancer, brain metastases, diffuse midline gliomas and primary central nervous system lymphoma. The company says the HR+/HER2- program could provide an opportunity to investigate whether paxalisib’s activity against PI3K/mTOR signaling and epigenetic resistance mechanisms can improve responses in patients whose disease has progressed after standard treatments. Importantly, the newly reported evidence remains preclinical, meaning its potential clinical benefit and safety in HR+/HER2- breast cancer still need to be established through human clinical testing.
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Source: Kazia Therapeutics press release
