TKI-ICI combo offers hope for prostate cancer patients with poor prognosis

A combination of the TKI* cabozantinib and ICI** atezolizumab improved progression-free survival (PFS) in men with metastatic castration-resistant prostate cancer (mCRPC) with measurable extrapelvic nodal or visceral metastasis who progressed on prior novel hormonal therapy (NHT), findings from the phase III CONTACT-02 trial have shown.

“Patients with mCRPC with prior progression on NHT and measurable soft tissue metastasis have a poor prognosis. The prognosis is even poorer in patients with visceral metastasis, especially those with liver metastasis,” said lead study investigator Dr Neeraj Agarwal from the Huntsman Cancer Institute at the University of Utah, Salt Lake City, Utah, US, at ASCO GU 2024.

After failure of NHT, chemotherapy or a second NHT are the only widely available nontargeted treatment alternatives for these patients, he continued. However, chemo is confounded by toxicity, frailty, and patient preference.

Therefore, this is a patient population with limited treatment options and thus a high unmet medical need, he said.

In the current analysis, there was a statistically significant PFS improvement in the PFS intention-to-treat (ITT) cohort after a median follow-up of 14.3 months, as evidenced by the 35-percent reduction in the risk of progression or death in patients on the cabozantinib-atezolizumab (C+A) combination vs those who received a second round of NHT (median 6.3 vs 4.2 months, hazard ratio [HR], 0.65; p=0.0007). [ASCO GU 2024, abstract 18]

The PFS benefit with the combo was observed across most prespecified subgroups, including those with liver metastasis (median 6.2 vs 2.1 months; HR, 0.43), bone metastasis (median 6.3 vs 4.1 months; HR, 0.67), and those who received prior docetaxel (median 8.8 vs 4.1 months; HR, 0.57).

“[Patients with liver metastasis] constituted nearly a quarter of the overall cohort and experienced a magnitude of benefit consistent with that seen in the overall population,” Agarwal noted.

Overall survival, safety outcomes

Data on overall survival (OS) are still immature (49 percent maturity) and did not meet the threshold for statistical significance. Still, the trend favoured C+A over NHT after a median follow-up of 12.0 months (median OS 16.7 vs 14.6 months; HR, 0.79; p=0.13). “The OS [with NHT] reflects the very poor prognosis of this population,” Agarwal said.

This effect was also seen among high-risk patient subgroups such as those with liver metastasis, prior docetaxel chemo, and bone metastasis (HRs, 0.60, 0.56, and 0.74, respectively).

“Grade 3/4 adverse events (AEs) were more common with C+A (48 percent vs 23 percent), but we did not see any new safety signals,” noted Agarwal. “This is consistent with those reported for this combo and other cabozantinib-ICI combinations that are widely used and approved in the community.”

The most common grade 3/4 AEs with C+A were hypertension (7 percent), anaemia (6 percent), diarrhoea (4 percent), and fatigue (4 percent).

Agarwal noted that despite the frequent dose reductions and modifications, only 13 percent of patients on C+A discontinued any component owing to AEs. “This is reflected by the high median dose intensity of cabozantinib (94 percent) and atezolizumab (83 percent).”

Other endpoints

Objective response rate was higher with C+A vs NHT (14 percent vs 4 percent), as was disease control rate (73 percent vs 55 percent).

Other key endpoints, such as median time to chemotherapy (HR, 0.56) and time to symptomatic skeletal events (HR, 0.62), tended to favour C+A over NHT.

“On the other hand, median time to deterioration in patient-reported quality of life (QoL) were similar, suggesting that C+A did not adversely impact QoL relative to second NHT in a patient population that was tolerant to the first NHT,” said Agarwal.

Expands treatment arsenal

The study randomized 507 participants (median age 71 years) 1:1 to C+A or a second NHT. Cabozantinib was given at a dose of 40 mg PO QD; atezolizumab at a dose of 1,200 mg IV Q3W. NHT could either be enzalutamide 160 mg PO QD or a combination of abiraterone 1,000 mg PO QD and prednisone 5 mg PO BID. Overall, about 80 percent of participants had bone metastasis, while 40 percent had visceral metastasis.

“CONTACT-02 is the first and only phase III trial of a TKI-ICI combination to show statistically significant improvement in PFS and a trend for OS in mCRPC patients. These data support C+A as a potentially new treatment option for patients with mCRPC who have progressed on NHT,” said Agarwal. Follow-up for OS is ongoing.

“[C+A] offers a unique clinically synergistic mechanism of action. This potentially expands the arsenal of treatment options for patients. Most importantly and refreshingly, this combo was active in subsets of patients that are most difficult to treat, eg, patients with aggressive features like visceral metastases,” commented ASCO Expert Dr Mark Fleming from the Brock Cancer Centre, Norfolk, Virginia, US, in a press release. [https://old-prod.asco.org/about-asco/press-center/news-releases/combination-cabozantinib-and-atezolizumab-offers-hope-patients]

“Given [the limited options for mCRPC patients] after progression on NHT, we recognize the need for a regimen that can delay disease progression, has an acceptable tolerability profile, and is widely available to patients who may not have the means or desire to travel to specialized centres for other therapies,” said Dr Amy Peterson, Chief Medical Officer at Exelixis. [https://ir.exelixis.com/news-releases/news-release-details/exelixis-announces-detailed-results-phase-3-contact-02-pivotal]

“Our decision to conduct CONTACT-02, based upon a signal we observed in COMET-01, underscores our commitment to patients with advanced prostate cancer and to improving their standard of care. We look forward to discussing these important results with the US FDA, and to learning more in the next analysis of OS anticipated this year,” Peterson added.