Abiraterone Before Chemo Improves Survival: Label Update

Roxanne Nelson, RN

April 01, 2015

The US Food and Drug Administration (FDA) has approved a label update for abiraterone acetate (Zytiga, Janssen Pharmaceuticals, Inc.), which now states that the drug significantly improves survival as compared with placebo when given before chemotherapy to men with metastatic castration-resistant prostate cancer (MCRPC).

Abiraterone had already been approved by the FDA for this indication, but the new label specifically mentions the survival benefit. The clinical data showing that benefit have recently been published.

Abiraterone first received FDA approval in April 2011 as a second-line treatment following docetaxel chemotherapy for patients with MCRPC. In December 2012, that indication was expanded to include use in the first-line setting on the basis of an interim analysis of a randomized phase 3 trial that showed that progression-free survival was significantly longer in the abiraterone group than in the placebo group.

The label update is based on the final analysis of that study, known as COU-AA-302, which has now been published in the Lancet Oncology.

At the time of the interim analysis, median overall survival had not yet been reached in the abiraterone group; it was 27.2 months in the placebo group.

The mortality rate was lower in the abiraterone group, however, than in the placebo group (27% vs 34%), with a 25% decrease in the risk for death (hazard ratio [HR], 0.75; P = .01), "indicating a strong trend toward improved survival," the study authors said at that time.

Now in the final analysis of the double-blind, placebo-controlled COU-AA-302 study, abiraterone plus prednisone significantly prolonged median overall survival compared with placebo plus prednisone in this population of chemotherapy-naive men with MCRPC.

After a median follow-up period of 49.2 months, men in the abiraterone group had a median overall survival of 34.7 months, as compared with 30.3 months in the placebo plus prednisone arm (HR = 0.81; 95% confidence interval [CI], 0.70 - 0.93; P = .0033).

"The statistically significant improvement in overall survival demonstrated in the final analysis and resulting label update help affirm the established efficacy, safety, and tolerability that physicians treating men with metastatic castration-resistant prostate cancer have seen with abiraterone," principal investigator Charles Ryan, MD, professor of clinical medicine and urology at the University of California, San Francisco, said in a statement.

"Representing a median follow-up of 4 years, this analysis adds to the robust body of clinical data supporting abiraterone as an important treatment option for men with metastatic castration-resistant prostate cancer."

Risk for Death Reduced

The study included 1088 asymptomatic or mildly symptomatic patients with chemotherapy-naive prostate cancer who were randomly assigned in a 1:1 ratio to receive either abiraterone acetate (1000 mg once daily) plus prednisone (5 mg twice daily) or placebo plus prednisone.

The focus of the current article was an update of overall survival and the secondary endpoint of time to opiate use for cancer-related pain.

At the time of the final analysis, 42 patients (8%) in the abiraterone group were still receiving treatment. A total of 238 (44%) patients in the placebo group subsequently went on to receive abiraterone, either as a crossover per protocol (93 patients) or as subsequent therapy (145 patients).

Overall, 365 (67%) patients in the abiraterone acetate group and 435 (80%) in the placebo group did receive subsequent treatment with one or more approved agents.

The risk for death was significantly lower in the abiraterone acetate group than in the placebo group (HR, 0.81; 95% CI, 0.70 - 0.93; P = .0033). The results on final analysis showed that 354 of 546 patients (65%) in the abiraterone acetate group had died, compared with 387 of 542 (71%) in the placebo group.

When looking at the secondary endpoint, patients in the abiraterone group had a longer interval to needing opiates for pain. The median time to opiate use for prostate cancer–related pain was 33.4 months in the abiraterone group vs 23.4 months in the placebo group.

The authors observed that there were no notable changes in the safety profile of abiraterone since the previous interim analyses were reported. The most common grade 3-4 adverse events of special interest were cardiac disorders (41 [8%] patients in the abiraterone group vs 20 [4%] in the placebo group), increased alanine aminotransferase levels (32 [6%] vs four [<1%]), and hypertension (25 [5%] vs 17 [3%]).

Time to Aim Higher

In an accompanying editorial, Ravi Madan, MD, and William L Dahut, MD, both of the National Cancer Institute, note that new treatment strategies are changing the paradigm of MCRPC.

They point out that during the past 5 years, there have been seven phase 3 trials, including this one, that have significantly extended survival in this patient population. The studies have used five different therapeutic modalities, including antiandrogens, chemotherapy, immunotherapy, and radiopharmaceuticals.

"This is a remarkable series of advancements that have substantially altered how metastatic castration resistant prostate cancer is treated," they write.

But now is the time to aim higher. "Although noteworthy delays of disease progression are valuable, an increase in the proportion of patients achieving cure is the ultimate goal," Dr Madan and Dr Dahut write.

They speculate as to whether abiraterone or any other emergent therapy can enhance the curative intent of radiation or surgery or whether it is possible to minimize mechanisms of resistance if tumor volume and heterogeneity are low at diagnosis.

"Fuelled by the remarkable revolution in therapies for metastatic castration-resistant prostate cancer, a new generation of clinical trials should bring these therapeutic advances to bear on the tumour when it is localised, with hopes of downstaging the disease before radiation or surgery," the editorialists suggest.

We should focus on finding ways to shift paradigms by using these therapies to enhance cure rates at diagnosis. Dr Ravi Madan and Dr William L Dahut

"We should no longer settle for shifting Kaplan-Meier curves in metastatic prostate cancer; instead, we should focus on finding ways to shift paradigms by using these therapies to enhance cure rates at diagnosis," they conclude.

The study was funded by Janssen Research and Development. Dr Ryan has received honoraria from Janssen Research and Development, and a number of the coauthors have also declared relationships with industry, including Janssen, as indicated in the article. The editorialists have reported no relevant financial relationships.

Lancet Oncol. Published online January 15, 2015. Abstract, Editorial


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