A New Prognostic Test for Patients with Metastatic CRPC

“In an analysis reported in the Journal of Clinical Oncology, Scher et al found that circulating tumor cell count and LDH level served as an individual-level surrogate for survival among patients with metastatic castration-resistant prostate cancer receiving abiraterone acetate (Zytiga) plus prednisone vs prednisone in the phase III COU-AA-301 trial.

“The double-blind COU-AA-301 trial included 1,195 patients previously treated with paclitaxel. The current analysis includes 711 patients (484 in the abiraterone-prednisone group, 227 in the prednisone group) with available 12-week biomarker data. Biomarker analysis was a secondary objective of the trial.

“The combination of circulating tumor cell count and LDH level at 12 weeks was shown to satisfy the four Prentice criteria for individual-level surrogacy (ie, treatment must have a significant effect on the clinical endpoint and a significant effect on the biomarker, the biomarker must have a significant impact on the endpoint, and the full effect of treatment on the endpoint must be captured by the biomarker)…

“The investigators concluded: ‘A biomarker panel containing [circulating tumor cell] number and LDH level was shown to be a surrogate for survival at the individual-patient level in this trial of abiraterone acetate plus prednisone versus prednisone alone for patients with metastatic [castration-resistant prostate cancer]. Additional trials are ongoing to validate the findings.’ ”


Lenalidomide Combination Fails to Improve Survival in Castration-Resistant Prostate Cancer

“The addition of lenalidomide to docetaxel and prednisone was associated with a significantly greater mortality rate in patients with metastatic castration-resistant prostate cancer, according to phase 3 study results.

“Daniel P. Petrylak, MD,professor of oncology and urology at Yale School of Medicine and a HemOnc Today Editorial Board member, and colleagues evaluated data from 1,046 chemotherapy-naive patients with metastatic castration-resistant prostate cancer.

“Researchers randomly assigned 525 patients to receive docetaxel and prednisone plus lenalidomide (Revlimid, Celgene). The other 521 patients received docetaxel and prednisone plus placebo.

“After a median follow-up of 8 months, 221 patients had died (lenalidomide arm, n = 129; placebo arm, n = 92). The number of deaths that occurred during treatment or within 28 days of receiving the final dose was similar in both groups (lenalidomide, n = 18; placebo, n = 13).”


Video: Dr. Higano on Radium-223 for mCRPC

“Celestia S. Higano, MD, FACP, professor of medicine and urology, University of Washington, discusses radium-223 chloride and its efficacy for patients with metastatic castration-resistant prostate cancer (mCRPC).

“Higano says radium-223 (Xofigo), a radium isotope recently approved by the FDA to treat mCRPC, is unique from other therapies in cancer overall. Results from a phase III study showed that patients who received radium-223 had higher overall survival (OS) compared to patients who did not receive the therapy.

“Radium-223 can also benefit patients who may have skeletal metastases, fractures, or require external beam radiation, Higano says.”

Click through to watch the video.


Orteronel Improved Progression Free Survival but Not Overall Survival in mCRPC

“In a phase III trial (ELM-PC 5) reported in the Journal of Clinical Oncology, Fizazi et al found that the addition of the 17,20-lyase inhibitor orteronel to prednisone in patients with metastatic castration-resistant prostate cancer progressing after docetaxel therapy resulted in an overall survival comparison that crossed the prespecified futility boundary at interim analysis. Orteronel treatment was associated with improved radiographic progression-free survival, prostate-specific antigen (PSA) reduction, and time to PSA progression.

“Orteronel targets the effects of CYP17A1, an enzyme important to androgen synthesis that exhibits 17α-hydroxylase and 17,20-lyase activities.

“In the double-blind trial, 1,099 men from 260 centers in 42 countries were randomly assigned  2:1 to receive orteronel at 400 mg plus prednisone at 5 mg twice daily (n = 734) or placebo plus prednisone at 5 mg twice daily (n = 365). The primary endpoint was overall survival…

“The investigators concluded: ‘Our study did not meet the primary end point of [overall survival]. Longer [radiographic progression-free survival] and a higher [≥ 50% PSA reduction] rate with orteronel-prednisone indicate antitumor activity.’ “


Progenics Pharmaceuticals Presents Positive Phase 2 Data for PSMA ADC in Metastatic Castration-Resistant Prostate Cancer

“Progenics Pharmaceuticals, Inc., (Nasdaq:PGNX) today announced the presentation of the full results from its Phase 2 clinical study of PSMA ADC in patients with metastatic castration-resistant prostate cancer (mCRPC), including new data from the recently completed chemo-naïve cohort. The data was presented in a poster session and was also selected for inclusion in the ASCO GU Audio Poster Tour at the American Society of Clinical Oncology Genitourinary Cancers (ASCO GU) Symposium, taking place from February 26 – 28, 2015 in Orlando, Florida.

” ‘The full data from this trial provides compelling evidence of the anti-cancer properties of PSMA ADC, with both the surrogate biomarker and radiological data suggesting a meaningful clinical benefit in progressive metastatic castration-resistant prostate cancer,’ stated Daniel Petrylak, M.D., Professor of Medical Oncology at Yale Cancer Center, Clinical Research Program Leader for the Prostate and Urologic Cancers Program at Smilow Cancer Hospital at Yale-New Haven, and lead investigator on the trial.

” ‘Although advances in androgen deprivation therapy, or ADT, have provided great benefit to prostate cancer patients, treatment options when ADT fails remain limited, which is why the results for PSMA ADC in this patient population are so encouraging. We observed shrinkage of patients’ tumors, the conversion of unfavorable levels of circulating tumor cells to favorable levels and the reduction in patients’ PSA scores, all of which provide strong evidence of PSMA ADC anti-tumor activity,’ said Mark Baker, CEO of Progenics.”


AR-V7 Biomarker Could Guide Treatment in mCRPC Patients

“In men with metastatic castration-resistant prostate cancer (mCRPC), the presence of androgen receptor V7 (AR-V7) in circulating tumor cells did not significantly affect response to treatment with taxane therapy, according to the results of a small prospective study (Abstract 138) presented at a press conference held in advance of the 2015 ASCO Genitourinary Cancers Symposium.

“In fact, researchers led by Emmanuel Antonarakis, MD, assistant professor of oncology and urology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, found that men who had AR-V7 detected in circulating tumor cells (AR-V7–positive) may retain their sensitivity to taxane-based treatment.

“An earlier study by Antonarakis and colleagues found that AR-V7–positive mCRPC patients treated with either enzalutamide or abiraterone fared worse than AR-V7–negative patients.

“AR-V7 is a truncated form of the androgen receptor that is detected in about one-third of patients with CRPC. AR-V7 lacks the ligand-binding domain of the androgen receptor, the target of enzalutamide and abiraterone.”


Docetaxel Was Widely Used to Treat Metastatic Prostate Cancer before Conclusive Evidence Showed Its Superiority

The gist: The drug docetaxel was widely used to treat patients with metastatic prostate cancer before phase III clinical trials showed it was better than standard treatment. This is significant for a few reasons. First, it shows that many doctors are willing to prescribe promising drugs “off-label,” before the U.S. Food and Drug Administration (FDA) has approved them  for treating certain conditions. It also shows that a drug that is used for one type of cancer is more likely to be prescribed off-label for other types of cancer. Some are concerned that off-label prescriptions undermine the clinical trial process and put some patients at risk by giving them drugs that may not turn out to be better.

‘Docetaxel was being widely used by patients with metastatic prostate cancer before phase III evidence that it was more effective than standard-of-care for patients with castration-resistant prostate cancer, according to an analysis of Medicare claims from before and after the trial results and approval of docetaxel by the U.S. Food and Drug Administration. The uptake of new treatments, or diffusion, “prior to definitive evidence indicates the prevalence of off-label chemotherapy use,” wrote Unger et al in the Journal of the National Cancer Institute

“Rapid and widespread use of docetaxel was not observed among all study participants receiving chemotherapy for metastatic prostate cancer. Statistically significant docetaxel uptake (P < .01) was seen in patients older than 65 years of age, blacks, patients in lower income areas, and those who experienced poverty. This observation ‘presents opportunities to improve the uptake of proven new therapies in subpopulations,’ the authors wrote, adding that direct-to-consumer advertising ‘could be a useful tool.’

Another potential method cited for encouraging more rapid adoption of new treatments was ‘enhancing communication channels among physicians, especially between key opinion leaders and their colleagues,’ the authors noted. ‘One factor that has been repeatedly identified to increase adoption rates is attendance at scientific symposia, which serve as forums for disseminating information about new treatments.’ ”


Zytiga with Prednisone Improves Survival in Castration-Resistant Prostate Cancer Patients

The gist: Adding the drug abiraterone acetate (Zytiga) to treatment with prednisone helps patients with castration-resistant prostate cancer (CRPC) live longer. The treatment was tested in patients in a clinical trial. Patients in the trial were treated between April 2009 and June 2010. The treatment appeared to lengthen the amount of time that patients lived without their disease worsening. In 2011, these promising results convinced the U.S. Food and Drug Administration (FDA) to approve Zytiga for treating metastatic castration-resistant prostate cancer patients who had not yet received chemotherapy. Now, in final analysis of data from the trial, researchers have shown that Zytiga lengthens life for these patients.

“In the final analysis of overall survival in the COU-AA-302 trial, reported in The Lancet Oncology by Ryan et al, the addition of abiraterone acetate (Zytiga) to prednisone significantly prolonged survival in chemotherapy-naive patients with castration-resistant prostate cancer. Abiraterone had been approved for use in this setting on the basis of improved radiographic progression-free survival in COU-AA-302.

“In this double-blind trial, 1,088 asymptomatic or mildly symptomatic patients were randomly assigned between April 2009 and June 2010 to receive abiraterone at 1,000 mg once daily plus prednisone at 5 mg twice daily (n = 546) or prednisone plus placebo (n = 542). The coprimary endpoints were radiographic progression-free survival and overall survival…

“The investigators concluded: ‘In this randomised phase 3 trial with a median follow-up of more than 4 years, treatment with abiraterone acetate prolonged overall survival compared with prednisone alone by a margin that was both clinically and statistically significant. These results further support the favourable safety profile of abiraterone acetate in patients with chemotherapy-naive metastatic castration-resistant prostate cancer.’ ”


Enzalutamide Outperforms Bicalutamide in Trial for Metastatic Castration-Resistant Prostate Cancer

The gist: In a clinical trial with metastatic, castration-resistant prostate cancer (CRPC) patients, the drug enzalutamide outperformed bicaluatmide. Men who took enzalutamide had about 10 more months without their disease worsening than men who took bicalutamide. 

“Medivation, Inc. MDVN, -3.90% and Astellas Pharma Inc. today announced topline results from the Phase 2 TERRAIN trial comparing enzalutamide with bicalutamide in men with metastatic castration-resistant prostate cancer. The study achieved its primary endpoint demonstrating a statistically significant increase in progression-free survival (PFS) for enzalutamide compared to bicalutamide (Hazard Ratio = 0.44; 95% Confidence Interval, 0.34-0.57; p < 0.0001). Median PFS was 15.7 months in the enzalutamide group compared to 5.8 months in the bicalutamide group.

“The median time on treatment in TERRAIN was 11.7 months in the enzalutamide group versus 5.8 months in the bicalutamide group. Serious adverse events were reported in 31.1% of enzalutamide-treated patients and 23.3% of bicalutamide-treated patients. Grade 3 or higher cardiac adverse events were reported in 5.5% of enzalutamide-treated patients versus 2.1% of bicalutamide-treated patients. Two seizures were reported in the enzalutamide group and one in the bicalutamide group. The most common side effects occurring during treatment and more common in the enzalutamide-treated versus bicalutamide-treated patients included fatigue, hot flush, hypertension, diarrhea, weight decreased and pain in extremity.

” ‘The results of this study showed that enzalutamide provides a longer duration of disease control in the studied patient population compared to bicalutamide,’ said Neal Shore, MD, co-principal investigator of the TERRAIN study and Medical Director, Carolina Urologic Research Center. ‘This robust data set adds to an impressive and consistent body of data for enzalutamide across multiple studies and stages of prostate cancer.’ “