Is This Prostate Cancer Drug Combo Beneficial Enough?

The combination of cabozantinib plus atezolizumab may extend progression-free survival (PFS) in patients with metastatic, castration-resistant prostate cancer (mCRPC), according to results from a phase 3 clinical trial presented at the 2024 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium. But is that two-month increase in PFS, which measures time without the cancer worsening, clinically meaningful?

What Did the CONTACT-02 Trial Show?

In the CONTACT-02 clinical trial, 507 patients with mCPRC that had progressed on novel hormonal therapy (NHT) were randomly assigned to receive the combination of cabozantinib plus atezolizumab or a second round of NHT. Cabozantinib is a tyrosine kinase inhibitor, while atezolizumab is an immune checkpoint inhibitor.

Novel hormonal therapies, such as abiraterone or enzalutamide, are a relatively new class of drugs that reduce testosterone activity even more than the drugs used for medical castration, said Stephen Freedland, MD, urologist and director of the Center for Integrated Research in Cancer and Lifestyle at the Cedars-Sinai Cancer Institute in Los Angeles.

After a median follow-up of 14.3 months, patients who received the drug combination had a median PFS of 6.3 months, compared with 4.2 months in the NHT group. Patients on the drug combination had a 35% reduction in their risk of progression or death relative to the NHT group.

What Was the Reaction from Experts?

“It's kind of, you know, good news, bad news, so to speak,” Dr. Freedland said of the results. “[The combination] delayed time until the disease progressed or patients died. That's a good sign, but the overall benefits in terms of delaying progression were very modest compared to what we typically see with other drugs in prostate cancer,” he said. Dr. Freedland, who was not a part of the trial, called the small increase in PFS “disappointing.”

“Castration-resistant” means that the cancer continues to grow after the testicles, which produce testosterone, are removed (surgical castration) or after hormone treatment to reduce testosterone production by the testicles (medical castration). Many prostate cancers that initially respond to hormone treatment eventually become castration resistant.

In the real world, according to an October 2023 study based on Medicare data and published in Prostate Cancer and Prostatic Diseases, survival of mCRPC is a little over two years (25.6 months). These patients, however, rarely received more than one round of treatment, said Dr. Freedland, who led that study.

The particular subset of patients included in CONTACT-02 has even lower survival, according to Neeraj Agarwal, MD, a medical oncologist who led CONTACT-02 and who directs the Genitourinary Oncology Program and the Center of Investigational Therapeutics at the University of Utah’s Huntsman Cancer Institute, in Salt Lake City.

In addition to having mCRPC, trial participants had to have progressed on NHT and to have cancer that had spread to the viscera (organs such as the liver) or to lymph nodes outside the pelvis. For these patients, survival is closer to one year, he said. In this context, Dr. Agarwal said, “to achieve a 35% reduction risk of progression or death is not only statistically significant, I think it's clinically meaningful.”

The benefit from the drug combination was particularly large in the subgroups of patients who had liver metastasis and those who had previously been treated with the chemotherapy docetaxel. In patients with liver metastases, the treatment group lived six months without progression or death compared with 2.1 months for the NHT group. In patients who had previously received docetaxel, participants in the treatment group lived 8.8 months without disease progression or death compared with 4.1 months in the NHT group. The number of patients with visceral metastases increases with each progression on each line of therapy, Dr. Agarwal noted.

“I am hoping the U.S. Federal Drug and Administration (FDA) will approve the combination soon so that these patients can benefit,” he said.

The researchers will continue to follow CONTACT-02 participants to report on overall survival, Dr. Agrawal said.

Takeaways

Dr. Freedland’s said there are two questions raised by these results: Will the FDA will approve the combination and whether doctors would want to offer the combination to their patients were it available. “I can't answer the FDA one. But I think the excitement that I heard in talking to people for this regimen was very low,” he said.

Dr. Freedland’s advice to patients is to keep participating in clinical trials. “I don't think this is going to change how we manage your cancer,” he said. “But use your cancer, your experience, as an opportunity to help us learn the right way of doing this so that we can make it better in the future.”