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SAN FRANCISCO -- Metastasis-free survival (MFS) more than doubled in men with castration-resistant prostate cancer (CRPC) treated with the androgen receptor signaling inhibitor enzalutamide (Xtandi), a large randomized trial showed.

Patients had a median MFS of 36.6 months with enzalutamide plus androgen deprivation therapy (ADT) versus 14.7 months with ADT and placebo. Progression events occurred half as often with enzalutamide, and each specific type of progression even occurred less often.

The interval to PSA progression increased 10-fold in the enzalutamide group, and time to initiation of new antineoplastic therapy more than doubled. An analysis of immature overall survival data showed a nonsignificant trend in favor of enzalutamide, as reported here at the (GUCS).

"The therapy was well tolerated, and adverse events were generally consistent with those reported in prior clinical trials of men with castration-resistant prostate cancer," said Maha Hussain, MD, of Northwestern University in Chicago. "Although median overall survival was not reached in either group in the first interim analysis, there was a 20% lower relative risk of death in the enzalutamide group."

The results mirrored those of another randomized trial reported at GUCS, showing more than a 70% reduction in the risk of metastatic progression in CRPC treated with a different androgen receptor signaling inhibitor, apalutamide.

In providing context for the two trials, invited discussant Philip Kantoff, MD, acknowledged that both studies yielded clearly positive results. However, he noted uncertainty surrounding the potential benefits of extending MFS.

"Treating asymptomatic patients carries a certain burden of proof, wherein benefit must clearly outweigh risk," said Kantoff, of Memorial Sloan Kettering Cancer Center in New York City.

Kantoff noted that an FDA advisory committee in 2012 voted against approval of the bone-targeted drug denosumab (Xgeva) for prevention of bone metastases in high-risk men with CRPC, as the chair of the committee called a radiographic benefit "a completely artificial endpoint."

Continuing the discussion, Kantoff cited three factors indicative of clinical benefit, and examined each one in the context of the two studies:

• Curing men -- probably not
• Prolonging survival -- not yet clear
• Improving quality of life -- some evidence from the apalutamide trial, which showed a reduction in skeletal-related events

Perhaps offsetting the QOL benefits is an increased risk of adverse events with more prolonged exposure to treatment, said Kantoff. Some of the adverse events have potentially serious consequences, such as falls and fractures, both of which occurred more often in the apalutamide (SPARTAN) study.

"These drugs are very biologically active," Kantoff said in conclusion. "This potentially gives us two new options for men with nonmetastatic CRPC. Delaying the onset of disease-related symptoms, as seen in SPARTAN, represents clinical benefit."

Hussain reported findings from the multicenter, randomized . The primary objective was to see whether the addition of enzalutamide to conventional ADT would improve MFS as compared with ADT alone for men with nonmetastatic CRPC, a disease that has no approved treatment.

The rationale for evaluating enzalutamide in the setting came from previous studies showing that treatment with the drug led to better overall and radiographic progression-free survival (rPFS) in men with and no prior chemotherapy and in patients with nonmetastatic CRPC and no prior chemotherapy.

Investigators in PROSPER randomized 1,401 men with nonmetastatic CRPC to enzalutamide plus ADT or placebo plus ADT at a ratio of 2:1. The trial had a primary endpoint of MFS, defined as the time from randomization to radiographic progression or death within 112 days of treatment discontinuation.

The study population had a median age of 73-74, median PSA of 10-11 ng/mL, and median PSA doubling time of <4 months. Three-fourths of the men had PSA doubling times <6 months, Hussain noted.

The trial ended after the first planned interim analysis when the data showed that patients in the enzalutamide group had a 71% reduction in the MFS hazard (95% CI 0.24-0.35, P<0.0001). Overall, 49% of patients in the placebo group and 23% in the enzalutamide arm had progression events (radiographic evidence or death). A subgroup analysis showed a consistent benefit for enzalutamide across all prespecified groups.

With regard to secondary endpoints, patients treated with enzalutamide had a median time to PSA progression of 37.2 months versus 3.9 months with placebo (HR 0.07, 95% CI 0.05-0.08, P<0.0001) and median time to new antineoplastic therapy of 39.6 versus 17.7 months (HR 0.21, 95% CI 0.17-0.26, P<0.0001).

After a median follow-up of about 22 months, the enzalutamide group had a nonsignificant trend toward better survival (HR 0.80, 95% CI 0.58-1.09).

Adverse events affected a similar proportion of patients in the two groups. Grade ≥3 adverse events occurred in 31% of the enzalutamide arm and 23% of the placebo arm. The most common grade ≥3 adverse events in the enzalutamide group were hypertension (5%), fatigue (3%), and hematuria (2%).

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