Advances in Treatment and Supportive Care

The Journal of Targeted Therapies in Cancer, August 2013, Volume 1, Issue 8

Long-term safety and efficacy results from COU-AA-302 in mCRPC, and efficacy and safety data for enzalutamide monotherapy were among the ASCO 2013 Annual Meeting presentations that extended clinically useful information for the care of patients with prostate cancer.

Neal D. Shore, MD

Long-term safety and efficacy results from COU-AA-302 in metastatic castration-resistant prostate cancer (mCRPC), a molecular characterization of patients more likely to benefit from abiraterone acetate, a pain analysis from the phase II ALSYMPCA study, and efficacy and safety data for enzalutamide monotherapy were among the American Society of Clinical Oncology (ASCO) 2013 Annual Meeting presentations that extended clinically useful information for the care of patients with prostate cancer.

In 2012, at a median follow-up of 22.2 months, COUAA- 302 investigators reported overall survival (OS), radiographic progression-free survival (rPFS), and secondary endpoints favorable for the abiraterone acetate (AA) arm, leading the Independent Data Monitoring Committee to recommend unblinding the study and offering all patients AA treatment.1The international COUAA- 302 trial assessed the clinical benefit of AA versus prednisone in 1088 mildly symptomatic or asymptomatic patients with progressive mCRPC.

At the 2013 ASCO Genitourinary Cancers Symposium, an updated analysis of COU-AA-302 upheld and extended the positive findings. According to lead author Dana E. Rathkopf, MD, from Memorial Sloan-Kettering Cancer Center in New York City, ata median of 27.1 months, OS, rPFS, and all secondary endpoints favored the AA treatment arm.2OS remained significantly superior in the AA arm, at 35.3 months versus 30.1 months in the prednisone control arm (hazard ratio [HR] = 0.79; 95% CI, 0.66-0.96;P<.0151). The updated analysis resulted in an expanded approval of AA for patients in the prechemotherapy setting for mCRPC.

Two studies from the ASCO 2013 meeting further elaborated upon the data on AA therapy in a group of patients with prostate cancer: In the final report on a long-term safety and efficacy analysis of COU-AA-302, at a median follow-up of 27.1 months, rPFS was significantly improved in patients receiving AA (HR = 0.53; 95% CI, 0.45-0.62;P<.0001). However, although OS was improved with AA over prednisone (HR = 0.79; 95% CI, 0.66-0.96;P=.0151), it did not reach the prespecified efficacy boundary (P=.0035).3

Co-investigator Neal D. Shore, MD, medical director of Carolina Urology Research Center in Myrtle Beach, South Carolina, commenting on these data, said, “We saw absolutely no new differences in safety signals or in toxicity parameters. But what we did see was a continued significant trend in survival. Although it did not meet a prespecified boundary, [there was] an obvious trend with aPvalue of .015. More important was the improvement in radiographic progression-free survival—almost a doubling from 8 months to 16 months in the treatment arm.”

Dana E. Rathkopf, MD

COU-AA-302 is the largest study to date to undertake a molecular characterization of participating CRPC patients. In a prospectively defined biomarker substudy, researchers conducted fluorescence in situ hybridization (FISH) assays to evaluateERGsubtypes.4ERGrearrangements result in androgen receptor—modulated upregulation ofERG, which may be predictive of response to AA in mCRPC.

Of 497 patients with tumor samples, 337 had FISH results that were evaluable. Of those, anERGrearrangement was present in 35% (117 of 337).

Summarizing the data arising from this analysis, Gerhardt Attard, MD, PhD, from the Institute for Cancer Research at the Royal Marsden NHS Foundation Trust, Sutton, UK, speaking on behalf of a group that included researchers from New York, California, and New Jersey, said that patients with chemotherapy-naïve mCRPC with a 2+ Ede1 rearrangement may derive a slightly greater benefit from AA and prednisone than other patients.

Gerhardt Attard, MD, PhD

In a phase II study in patients with hormone-naïve prostate cancer, the oral androgen receptor (AR) inhibitor enzalutamide achieved a “high response rate and marked PSA decline,” with efficacy similar to castration but without the side effects of androgen-deprivation therapy. During the 6-month, single-arm trial, bone mineral density remained stable, and metabolic variables such as fat body mass, lipid profiles, and glycemic profiles did not show substantial changes.5

Matthew R. Smith, MD, PhD, from Massachusetts General Hospital Cancer Center in Boston, along with a group of researchers from Belgium, Denmark, and Germany, assessed enzalutamide monotherapy at the approved dosage of 160 mg per day for 25 weeks in patients with hormone-naïve prostate cancer and noncastrate testosterone (T) ≥230 ng/dL (N = 67). The primary endpoint was PSA response, defined as ≥80% decline at the study’s end.

“We know that a lot of patients will need androgendeprivation therapy,” said principal investigator Bertrand Tombal, MD, PhD, professor and chairman, Department of Urology, Cliniques Universitaires Saint-Luc, Brussels, Belgium, speaking at ASCO 2013 about the study and its implications. “In Europe, we have been using androgen monotherapy… and these drugs have the ability to control the cancer without requiring androgen-deprivation therapy.” The goal is to develop an alternative to standard hormone therapy.

“We took a really conservative approach in these patients…showing a PSA drop of more than 80%, to be sure, at least, that if it didn’t reach that endpoint, we would know that we couldn’t go further. In fact, it did much better than that, depressing PSA very, very profoundly. Anti-androgen monotherapy is not an unfinished business,” Tombal added. However, there are promises for patients in a few years for a drug that could do the same as androgen-deprivation therapy without the side effects.

Bertrand Tombal, MD, PhD

Asked about a key message for clinicians today, Tombal said, “Look at these drugs and try to think outside the box of standard hormonal therapy.”

Ra-223 is an alpha-particle-emitting radiotherapeutic drug that mimics calcium and forms complexes with hydroxyapatite at areas of increased bone turnover, such as bone metastases. The potential of this radiotherapeutic agent was revealed in an earlier phase II dose-response study, where investigators found that a single injection of Ra-223 induced a pain response (pain relief) in up to 71% of patients with CRPC who had painful bone metastases.

In addition to prolonging survival in the large (N = 921) phase III ALSYMPCA study, radium-223 (Ra-223) reduced pain and opioid use in patients with CRPC with bone metastases, in a post hoc pain analysis reported by Sten Nilsson, MD, PhD,from the University of Oslo, Norway, at ASCO 2013.6

Accordingly, in the phase III ALSYMPCA study, researchers randomized patients with CRPC with bone metastases 2:1 to receive six injections of Ra-223 (n = 614) or placebo (n = 307). The Cox proportional hazards model was used for an analysis of time to initial opioid use and time to external-beam radiation therapy (EBRT). Pain-related quality of life (QoL) was analyzed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) subscale, using ANCOVA. At baseline, approximately 55% of enrolled ALSYMPCA patients had moderate- to-severe pain and opioid use, based on the World Health Organization ladder for cancer pain.

The median time to opioid use was significantly longer in the Ra-223 group, with a risk reduction of 38% versus placebo (HR = 0.621; 95% CI, 0.456-0.846). Fewer Ra- 223-treated patients required opioids for pain relief than placebo-treated patients (36% vs 50%, respectively). At week 16, the QoL pain score reflected significant reductions in pain among the Ra-223-treated group (P=.001). On May 15, 2013, the FDA approved radium-223 dichloride (Xofigo) for the treatment of patients with CRPC, symptomatic bone metastases, and no known visceral metastatic disease.


1. Ryan CJ, Smith MR, DeBono JS, et al. Interim analysis (IA) results of COUAA- 302, a randomized, phase III study of abiraterone acetate (AA) in chemotherapy-naïve patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).J Clin Oncol. 2013;31(suppl; abstr LBA4518).

2. Rathkopf DE, Smith MR, DeBono JS, et al. Updated interim analysis (IA) of COU-AA-302, a randomized phase III study of abiraterone acetate (A) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) without prior chemotherapy. Presented at: 2013 ASCO Genitourinary Cancers Symposium; February 14-16, 2013; Orlando, FL. Abstract 5.

3. Rathkopf DE, Smith MR, DeBono JS, et al. Long-term safety and efficacy of abiraterone acetate (AA) plus prednisone (P) in metastatic castrationresistant prostate cancer (mCRPC) without prior chemotherapy (COUAA- 302).J Clin Oncol. 2013;31(suppl; abstr 5009).

4. Attard G, DeBono JS, Li W, et al.ERGrearrangements and association with clinical outcome in patients (pts) receiving abiraterone acetate (AA): results from the COU-AA-302 study in chemotherapy (chemo)-naïve metastatic castration-resistant prostate cancer (mCRPC).J Clin Oncol. 2013;31(suppl; abstr 5004).

5. Smith MR, Borre M, Rathenborg P, et al. Efficacy and safety of enzalutamide (ENZA) monotherapy in hormone-naïve prostate cancer (HNPC).J Clin Oncol. 2013;31(suppl; abstr 5001).

6. Nilsson S, Sartor AO, Bruland OS, et al. Pain analyses from the phase III randomized ALSYMPCA study with radium-223 dichloride (Ra-223) in castration-resistant prostate cancer (CRPC) patients with bone metastases.J Clin Oncol