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SAN FRANCISCO -- In patients with metastatic castration-resistant prostate cancer (mCRPC) whose disease progressed on a novel hormonal therapy, the combination of cabozantinib (Cabometyx) plus atezolizumab (Tecentriq) improved radiographic progression-free survival (rPFS) versus a switch to a second hormonal agent, a phase III trial showed.

The so-called CONTACT-02 study included patients with extrapelvic nodal or visceral metastasis with disease progression after either abiraterone (Zytiga) or enzalutamide (Xtandi).

Median rPFS reached 6.3 months for patients assigned to cabozantinib-atezolizumab versus 4.2 months for those switched to the opposite hormonal agent (HR 0.65, 95% CI 0.50-0.84, P=0.0007), a "clinically meaningful improvement," according to Neeraj Agarwal, MD, of the Huntsman Cancer Institute at the University of Utah in Salt Lake City, who presented the findings here.

A trend for overall survival (OS) favored the cabozantinib-atezolizumab arm (16.7 vs 14.6 months, respectively; HR 0.79, 95% CI 0.58-1.07, P=0.13), though these data were immature at the time of the analysis, he reported at the Genitourinary Cancers Symposium.

This is the first phase III study of a tyrosine kinase inhibitor (TKI) plus immune checkpoint inhibitor (ICI) combination to show a significant PFS improvement in mCRPC, said Agarwal, who added that the data support cabozantinib-atezolizumab as a potential new treatment option for a population with a very poor prognosis.

However, invited-discussant Kim N. Chi, MD, of the British Columbia Cancer Agency in Vancouver, said he personally could not recommend the combination, "given the data that we've seen and the better options that are available for this patient population."

Chi called the rPFS benefit only modest and cited a host of study limitations, including a lack of clarity on the specific contribution of cabozantinib and atezolizumab. "Don't forget that cabozantinib monotherapy had an rPFS benefit previously described of 6.6 months in a more heavily pretreated population," he said.

Control Arm Questioned

Chi also questioned the choice of control arm, saying that an androgen receptor pathway inhibitor (ARPI) switch is "not the best standard of care for this patient population with measurable disease and 40% visceral metastases."

"There are better options," he said, noting that docetaxel and cabazitaxel have shown PFS rates of 8-9 months in phase III trials.

Agarwal said chemotherapy use is often limited in this patient population due to concerns about toxicity, frailty, and patient preference, however.

When asked how investigators chose the control arm for the trial, he noted that real-world studies have shown that mCRPC patients are less likely to accept chemotherapy, and that novel hormonal therapy (NHT; i.e., ARPIs) has never been tested against docetaxel in a randomized controlled trial after NHT failure. "Based on these two factors, regulatory bodies across the world have accepted alternative NHT as a control arm."

As for the possibility of using cabozantinib alone in the control arm, Agarwal noted that it failed to significantly improve OS in the phase III , and that would have made it challenging as a control arm when trying to convince institutional review boards.

Study Details

randomized 507 mCRPC patients 1:1 to receive either oral cabozantinib once daily plus IV atezolizumab every 3 weeks or second-line NHT with either oral abiraterone plus prednisone or oral enzalutamide once a day.

Median age was 71 years and patients had a median baseline prostate-specific antigen (PSA) level of 25-34 ng/mL. About 80% of patients had bone metastases and about 75% had enlarged lymph nodes.

Agarwal noted that the combination was particularly effective in two prespecified subgroups of special interest, patients with liver metastases and those with prior docetaxel:

• Liver metastases: median rPFS of 6.2 vs 2.1 months (HR 0.43, 95% CI 0.27-0.68)
• Prior docetaxel: 8.8 vs 4.1 months (HR 0.57, 95% CI 0.34-0.97)

The objective response rate was 14% with the combination versus 4% with second NHT, with 1% of patients in the combination arm achieving a complete response.

As for safety, grade 5 treatment-emergent adverse events (TEAEs) occurred in 9% and 12% of the combination and NHT arms, respectively, and no grade 5 TEAEs occurred in either arm. TEAEs led to the discontinuation of all treatment components in 16% of the combination arm and 15% of NHT-switch arm.

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