How Paxalisib Is Being Studied in Treatment-Resistant Breast Cancer

Treatment resistance remains a challenge for patients with advanced hormone receptor (HR)-positive, HER2-negative breast cancer, particularly when the disease progresses after endocrine therapy and CDK4/6 inhibitors.

Kazia Therapeutics is expanding an ongoing clinical trial of paxalisib into this patient population after preclinical research suggested the drug may help resensitize treatment-resistant tumors to CDK4/6 inhibitors. The study will evaluate paxalisib in combination with fulvestrant and palbociclib, with safety and tolerability as key objectives.

The findings supporting this approach are still preclinical, meaning researchers do not yet know whether the same effects will occur in patients.

In a Q&A with CURE, Dr. John Friend, CEO of Kazia Therapeutics, discussed the biology behind the approach, how researchers are studying biomarkers and what patients should know about the trial.

CURE: For patients with HR-positive, HER2-negative breast cancer, what happens when the cancer stops responding to treatments such as CDK4/6 inhibitors? How could paxalisib potentially help?

Friend: HR-positive, HER2-negative breast cancer makes up the majority of breast cancer cases, but there is still a lot of room for improvement. Endocrine therapies and CDK4/6 inhibitors have transformed treatment, particularly in advanced disease, but we know patients can eventually develop resistance and their cancer can progress.

With paxalisib, our preclinical models showed not only a direct antitumor effect, but also evidence that the drug may resensitize tumors so CDK4/6 inhibitors can become effective again.

That was an important finding for us because it suggested paxalisib may be doing more than inhibiting the PI3K/mTOR pathway. We saw evidence that it may also affect biological programs associated with treatment resistance, immune evasion and metastatic behavior.

What can the preclinical findings suggest about how paxalisib may work in patients?

That distinction is very important. Preclinical data come from laboratory and disease models. They help us understand the biology, develop hypotheses and determine whether there is enough evidence to bring an approach into a clinical trial.

They do not guarantee that we are going to see the same results in patients.

We have seen these findings across different experimental settings, including cell cultures, animal studies and blood samples, which is encouraging. But ultimately, translating those findings into a clinical trial is why we conduct these studies.

Paxalisib has also already been studied in more than 550 patients across our brain cancer programs, so we have experience with its safety and tolerability. What we now need to test is whether the biological effects we have observed in HR-positive, HER2-negative breast cancer will translate into clinical benefit.

What could research studies on biomarkers in blood and tumor tissue show?

We don't want to simply start a trial without understanding how paxalisib is working or whether there are particular patients who may be more likely to benefit.

Blood and tissue samples may help us identify biomarkers or mutations associated with response. If we can identify a group of patients in whom this biology is particularly important, that could eventually help us better select patients for treatment.

One feature of paxalisib is that it was originally designed to cross the blood-brain barrier. Our research also suggests it may enter areas within cancer cells, including the nucleus, that other therapies may not reach in the same way.

We want to investigate whether those properties are connected to the effects we are seeing on treatment resistance and whether blood or tissue markers can help us detect those effects.

The trial includes paxalisib with fulvestrant and palbociclib, as well as a comparator arm. How will researchers determine whether paxalisib is adding benefit?

Safety and tolerability are the primary objectives because this will be the first time we are evaluating paxalisib in this combination and in this particular patient population.

These are patients whose cancer has already been exposed to first-line treatment, including endocrine therapy and CDK4/6 inhibition, and whose disease has progressed.

The study will look at two different doses of paxalisib combined with fulvestrant and palbociclib, as well as a comparator arm with fulvestrant. Having that comparator is important because it allows us to investigate whether adding paxalisib provides additional benefit.

One of the questions we especially want to answer is whether paxalisib can resensitize tumors that have developed resistance to CDK4/6 inhibition.

Who will be eligible for the HR-positive, HER2-negative expansion, and will patients in the United States be able to enroll?

The current triple-negative breast cancer trial is enrolling in Australia, and we are adding the HR-positive, HER2-negative arm to that ongoing study.

Initially, the expansion will also be available in Australia. These will be patients with metastatic HR-positive, HER2-negative breast cancer who have already received first-line therapy and whose disease has progressed.

We do intend to expand the study into additional countries, including the United States. Specific eligibility will be determined by the study protocol.

What should patients watch for next as this research moves forward?

The next step is really testing what we have learned in the laboratory in patients.

We are also continuing to study blood and tissue samples to understand whether there are biomarkers that could predict which patients are most likely to respond.

Presenting these findings at scientific meetings and publishing the results will also be important. We expect additional data to come from the program as the study progresses.

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