Kazia's Paxalisib: A Dual Threat to Breast Cancer's Metastatic Engine

SYDNEY, Australia – December 10, 2025 – In the high-stakes world of oncology, true breakthroughs often come not from incremental improvements but from fundamentally altering the rules of engagement. This week, at the prestigious San Antonio Breast Cancer Symposium (SABCS), Australian biotech Kazia Therapeutics presented data that does just that. The findings on its lead drug, paxalisib, suggest a paradigm shift in how we might combat the most aggressive forms of breast cancer, targeting not just the primary tumor, but the very mechanism of its deadly spread.

For investors and executives tracking market disruptors, Kazia’s announcement is more than just promising clinical news. It represents a strategic masterstroke, potentially repositioning a drug known primarily for brain cancer into a pivotal player in the multi-billion-dollar advanced breast cancer arena. The data reveals a unique dual-action mechanism that addresses two of the most significant challenges in modern oncology: metastatic spread and immunotherapy resistance.

Deconstructing the Metastatic Engine

For years, oncologists have understood that the primary tumor is often not the ultimate cause of mortality. The real danger lies in metastasis, a process driven by circulating tumor cells (CTCs) that break away, travel through the bloodstream, and seed new tumors in distant organs. Even more perilous are CTC clusters—micro-clumps of cancer cells that are exponentially more effective at forming metastases than single cells. Current therapies, even highly effective ones, often fail to eliminate this residual threat.

This is the “biological gap” that paxalisib appears to fill. New ex vivo data presented at SABCS, derived from patients with HER2-positive metastatic breast cancer, is striking. Even in patients whose tumors were shrinking in response to standard HER2-targeted therapies, their blood still harbored these highly aggressive CTC clusters. When treated with paxalisib, however, single CTCs were reduced by 42% and, critically, the more dangerous CTC clusters were decimated by 78%.

“These findings reveal an important biological gap left by existing HER2+ directed therapies,” noted Prof. Sudha Rao of QIMR Berghofer in the company’s announcement. “CTC clusters persist even in responding patients, and paxalisib is the first agent we have observed that can directly dismantle this highly aggressive and clinically relevant compartment.” By disrupting CTCs marked with aggressive mesenchymal proteins like Vimentin and Snail, paxalisib is not just cleaning up leftover cells; it is actively dismantling the machinery of metastatic progression.

A Clinical Glimpse of Power

Translating lab findings into clinical reality is the crucible where most drugs fail. However, the first trickle of data from Kazia’s PaxPlus-ABC Phase 1b study in triple-negative breast cancer (TNBC) provides a powerful, if early, validation of the drug's mechanism. Data from the very first patient treated with paxalisib in combination with immunotherapy and chemotherapy is compelling.

After just one cycle, the patient experienced a remarkable 76% reduction in primary tumor volume. But the more profound story was told through liquid biopsy. The treatment led to a marked reduction in CTC clusters and an epigenetic reprogramming of the remaining cancer cells toward a less aggressive state. In essence, the drug was taming the cancer at a cellular level.

A serendipitous event during the trial provided the most telling evidence of paxalisib's unique role. The patient had to temporarily pause paxalisib due to a chemotherapy-related side effect, while continuing the immunotherapy pembrolizumab (Keytruda). Almost immediately, the dangerous CTC clusters came roaring back. Upon resuming paxalisib just three weeks later, the clusters were once again suppressed. This on-off-on dynamic strongly indicates that paxalisib is the essential component for controlling these metastatic drivers—a task that a blockbuster checkpoint inhibitor like Keytruda could not accomplish on its own.

The 'Cold to Hot' Immune Revolution

The second pillar of paxalisib’s disruptive potential lies in its ability to reinvigorate a patient's own immune system. One of the great frustrations with modern immunotherapies is that they are ineffective against “cold” tumors—cancers that are not recognized by the immune system. A key reason for this is T-cell exhaustion, where the body's cancer-fighting cells become worn out and dysfunctional.

The new data shows paxalisib directly counters this. In both the HER2+ and TNBC datasets, paxalisib treatment was shown to reverse T-cell exhaustion, reactivating cytotoxic pathways and waking up the immune response. By reducing exhausted CD8 T cells and boosting inflammatory signaling, it effectively turns a “cold,” immune-ignorant tumor environment into a “hot” one that is ripe for attack by both the body's natural defenses and checkpoint inhibitor drugs.

This positions paxalisib not as a competitor to immunotherapies, but as a crucial enabler. For pharmaceutical giants with blockbuster checkpoint inhibitors, combination strategies that expand their efficacy into new patient populations are the holy grail. Paxalisib’s ability to prime the tumor microenvironment makes it an exceptionally attractive partner, creating significant strategic value by potentially making existing multi-billion dollar drugs work better and for more patients.

A Strategic Expansion Beyond the Brain

Until now, Kazia Therapeutics has been largely defined by paxalisib’s development in glioblastoma, a notoriously difficult-to-treat brain cancer. While that program continues to advance toward a pivotal study, this new breast cancer data represents a massive expansion of the drug's potential horizon.

“Paxalisib appears capable of disrupting metastatic machinery that is not adequately addressed by current HER2-targeted therapies, checkpoint inhibitors, or chemotherapies,” stated Dr. John Friend, CEO of Kazia Therapeutics. He highlighted the “unifying biology” across different cancer types, suggesting the drug’s mechanism is broadly applicable.

This strategic diversification could not come at a better time. Kazia recently shored up its balance sheet with a $50 million private placement, providing a cash runway into 2028. This capital gives the company the resources to aggressively pursue these new indications. For a small biotech, demonstrating a clear mechanism of action in two of the most challenging subtypes of breast cancer—a market far larger than glioblastoma—fundamentally changes its value proposition.

While the journey is far from over—the data is from early-stage trials and needs validation in larger patient cohorts—the strategic implications are clear. Kazia has uncovered a potential vulnerability in the armor of advanced breast cancer. By targeting the metastatic engine and reigniting the immune system, paxalisib is no longer just a brain cancer drug; it is a market disruptor with the potential to reshape treatment paradigms across oncology.