New Data Provide Insight Into Optimal Pre-Chemo Treatments for mCRPC

The combination of abiraterone acetate and prednisone has demonstrated a statistically significant improvement in overall survival (OS) for men with metastatic castration-resistant prostate cancer (mCRPC) who had not received prior treatment with chemotherapy

Charles J. Ryan, MD

The combination of abiraterone acetate and prednisone has demonstrated a statistically significant improvement in overall survival (OS) for men with metastatic castration-resistant prostate cancer (mCRPC) who had not received prior treatment with chemotherapy, according to a long-term follow-up of the phase III COU-AA-302 trial that was presented at the 2014 ESMO Congress.1

"OS is particularly noteworthy in COU-AA-302, because 67% of men in the Zytiga plus prednisone arm and 80% in the control arm received subsequent therapy," lead investigator Charles Ryan, MD, a professor of Clinical Medicine and Urology at the University of California, San Francisco, said in a statement. "This includes 44% of men in the control arm who subsequently received Zytiga plus prednisone."

The FDA approved abiraterone as a treatment for untreated men with mCRPC in December 2012. The approval was based on improvement in median radiographic progression-free survival (rPFS), time-to-opiate, and time-to-cytotoxic chemotherapy in patients treated with abiraterone. At the time, data from the third-interim analysis of the COU-AA-302 study did not cross the threshold for statistical significance.

In the study, 1088 patients were randomized in a 1:1 ratio to abiraterone plus prednisone or prednisone and placebo. Abiraterone was administered at 1,000 milligram once daily and prednisone was administered at 5 mg twice daily. The co-primary outcome measures were rPFS and OS.

In updated findings from a median 49.4-month final analysis, the median OS with abiraterone was 34.7 months versus 30.3 months with placebo (HR = 0.80; 95% CI, 0.69-0.93; P = .0027). The O'Brien-Fleming boundary for statistical significance was set as 0.0384.

"The use of subsequent therapies did not impact the statistical significance between the Zytiga and control arms—and makes these results all the more compelling after adjusting for the crossover effect," Ryan said.

The updated analysis also impacted data on the median time to opiate use. The updated median time with abiraterone was 33.4 months versus 23.4 months with placebo (HR = 0.72; 95% CI, 0.61-0.85; P = .0001).

Adverse events were similar at the updated analysis. The authors noted that the most common side effects of interest with abiraterone were grade 3/4 hypertension (4.6% vs 3.1%), hypokalemia (2.6% vs 1.9%), ALT increase (5.9% vs 0.7%), AST increase (3.3% vs 0.9%); fluid retention/edema (1.1% vs 1.7%).

"Since the first report of interim data, Zytiga has become a key part of the treatment arsenal that doctors use to treat mCRPC, because it significantly delayed the progression of the disease and prolonged overall survival," Ryan said. "This final analysis also demonstrates a consistent safety profile with long-term coadministration of prednisone."

The FDA recently approved enzalutamide (Xtandi) as a treatment for men with chemotherapy-naive mCRPC on September 10, 2014. This decision was based on data from the phase III PREVAIL trial that demonstrated an extension in OS and rPFS in 1717 men treated with the drug.

In this trial, the median OS was 32.4 months with enzalutamide versus 30.2 months with placebo (HR = 0.71; P <.0001). The median rPFS was not yet reached in the enzalutamide arm compared with 3.9 months with placebo (HR = 0.19; P <.0001), according to data published in The New England Journal of Medicine (NEJM).2

“In future trials it will be important to select patients responsive versus resistant to abiraterone or other anti-androgen agents,” Giuseppe Curigliano, MD, PhD, the co-chair of the Division of Medical Oncology at European Institute of Oncology, in Milan, Italy, said about the findings.

In a study presented at the 2014 ESMO Congress and published in NEJM, researchers explored circulating tumor cells (CTCs) from patients with mCRPC starting treatment with either enzalutamide or abiraterone.3 This study found an association between the splice variant AR-V7 with resistance to enzalutamide and abiraterone.

"Until now, we haven't been able to predict which patients will not respond to these therapies,” lead investigator Emmanuel Antonarakis, MD, an assistant professor of oncology at Johns Hopkins, said in a statement. “If our results are confirmed by other researchers, a blood test could use AR-V7 as a biomarker to predict enzalutamide and abiraterone resistance, and let us direct patients who test positive for AR-V7 toward other types of therapy sooner, saving time and money while avoiding futile therapy."

Among men receiving enzalutamide (n = 31), AR-V7—positive patients (39%) had lower PSA response rates than AR-V7–negative patients (0% vs 53%; P = .004); shorter clinical or radiographic PFS (median 2.1 vs 6.1 months; P <.001); and OS (median 5.5 vs not reached; P = .002).

Among men receiving abiraterone (n = 31), AR-V7—positive patients (19%) had lower PSA response rates than AR-V7–negative patients (0% vs 68%; P = .004); shorter clinical or radiographic PFS (median 2.3 vs not reached; P <.001); and OS (median 10.6 months vs not reached; P = .006).

"Patients whose blood samples contained AR-V7 got no benefit from either enzalutamide or abiraterone," said Antonarakis. "This test could be used before starting enzalutamide or abiraterone therapy, and if the test shows the presence of AR-V7, patients may opt for a different therapy. It could also be used to monitor patients receiving enzalutamide or abiraterone for AR-V7, providing an indication these drugs may not work for much longer."

References

  1. Ryan C, Smith M, Fizazi K, et al. Final overall survival (OS) analysis of COU-AA-302, a randomized phase 3 study of abiraterone acetate (AA) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) without prior chemotherapy. Presented at: ESMO Congress 2014: September 26-30, 2014. Abstract 753O.
  2. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in Metastatic Prostate Cancer before Chemotherapy [published online ahead of print July 31, 2014]. N Engl J Med. doi:10.1056/NEJMoa1405095.
  3. Antonarakis ES, Lu C, Wang H, et al. AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer [published online ahead of print October 11, 2014]. N Engl J Med. doi:10.1056/NEJMoa1315815

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