At the 2013 ASCO Annual Meeting, researchers presented the latest developments with enzalutamide, radium-223, and abiraterone acetate as treatments for patients with advanced prostate cancer.
Bertrand Tombal, MD, PhD
Efficacy and safety data for enzalutamide (Xtandi) monotherapy; a pain analysis from the phase III ALSYMPCA study of radium-223 (Xofigo); long-term safety and efficacy results from the COU-AA-302 study of abiraterone acetate (Zytiga); and a molecular characterization of patients more likely to benefit from abiraterone acetate are among the many presentations at the 2013 ASCO Annual Meeting that provided clinically useful information for the care of patients with prostate cancer.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.1 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.
The researchers assessed enzalutamide monotherapy at the approved dose of 160 mg per day for 25 weeks in patients with hormone-naïve prostate cancer and noncastrate testosterone ≥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 androgen- deprivation therapy,” said principal investigator Bertrand Tombal, MD, PhD, professor and chairman, Department of Urology, Cliniques Universitaires Saint-Luc, Brussels, Belgium, in a presentation at ASCO 2013. “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. “Antiandrogen monotherapy is not an unfinished business,” Tombal added. But 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.
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.”The FDA approved radium-223 dichloride (radium- 223; Xofigo) in May for the treatment of patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases, and no known visceral metastatic disease. The decision was based on results from the phase III ALSYMPCA study. A post hoc pain analysis of ALSYMPCA reported at ASCO 2013 by Sten Nilsson, MD, PhD, from the University of Oslo, Norway, found that in addition to prolonging survival, radium-223 reduced pain and opioid use in patients with CRPC and bone metastases.2
Radium-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. In ALSYMPCA, patients with CRPC with bone metastases were randomized 2:1 to six injections of radium-223 (n = 614) or placebo (n = 307).
The Cox proportional hazards model was used by Nilsson et al for an analysis of time to initial opioid use and time to external-beam radiation therapy. Pain-related quality of life (QoL) was analyzed using the Functional Assessment of Cancer Therapy-Prostate subscale, using ANCOVA.
At baseline, approximately 55% of 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 radium-223 group, with a risk reduction of 38% versus placebo (hazard ratio = 0.621; 95% CI, 0.456-0.846). Fewer patients who received radium-223 required opioids for pain relief than placebo-treated patients (36% vs 50%, respectively). And at week 16, the QoL pain score reflected significant reductions in pain among the radium-223 group (P = .001).The international COU-AA-302 trial assessed the clinical benefit of abiraterone acetate (AA) plus prednisone versus prednisone alone in 1088 chemotherapy- naïve mildly symptomatic or asymptomatic patients with progressive metastatic CRPC (mCRPC). The study was the basis for the FDA’s decision in December to expand the indication of AA to the prechemotherapy setting for mCRPC.
In the final report on long-term safety and efficacy analysis of COU-AA-302 presented at ASCO 2013, lead author Dana E. Rathkopf, MD, Memorial Sloan-Kettering Cancer Center, said that at a median follow-up of 27.1 months, radiographic progression-free survival was significantly improved in patients receiving AA (HR = 0.53; 95% CI, 0.45-0.62; P <.0001).3 However, although overall survival was improved with AA over prednisone (HR = 0.79; P =.0151), it did not reach the prespecified efficacy boundary (P =.0035).
Neal D. Shore, MD
Co-investigator Neal D. Shore, MD, medical director of Carolina Urology Research Center in Myrtle Beach, North 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 a P value 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.”The ERG gene encodes for the protein ERG, which functions as a transcriptional regulator. ERG rearrangements result in androgen receptor-modulated upregulation of ERG, which may be predictive of response to AA in mCRPC. In a prospectively defined biomarker substudy also presented at ASCO 2013, COU-AA-302 investigators conducted fluorescence in situ hybridization (FISH) assays to evaluate patients’ ERG subtypes.4
Of 497 patients with tumor samples, 337 had FISH results that were evaluable. Of the evaluable samples, an ERG rearrangement 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, 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.