Failure of ELM-PC 5: an ineffective drug or an unfit end point?

The ELM-PC 5 (Evaluation of the Lyase Inhibitor Orteronel in Metastatic Prostate Cancer 5; NCT01193257) study, the report of which accompanies this editorial, is a negative trial, will not change practice, and may seem inconsequential. However, this study should provoke significant unease. The question posed by the ELM-PC 5 trial was whether orteronel (TAK-700) is simply ineffective or whether it is active, and this is the first indication that the end point of overall survival (OS) is no longer fit for use for phase III clinical trials involving men with metastatic castration-resistant prostate cancer (mCRPC). The roots of the OS issue trace to the watershed years of 2004 and 2010. In 2004, docetaxel was shown to be the first drug to prolong OS for men with mCRPC. Subsequently, clinical trials for mCRPC were divided, largely for regulatory reasons, between those enrolling men who had not yet received docetaxel and those enrolling men who had. Many of these trials were placebo controlled, because the latter group had no life-prolonging choices available, and the former had only docetaxel, which could be administered after study. Patients and investigators accepted these designs and also accepted that early signs of progression did not necessarily represent the end of treatment benefit. To minimize the premature discontinuation of potentially beneficial therapy, treatment was continued through biochemical progression until either radiographic or clinical progression, significantly increasing the quality of these trials. In this era, OS was a feasible and reasonable end point, and this generation of studies ultimately yielded, in rapid succession, five drugs that met an OS end point: sipuleucel-T, cabazitaxel, abiraterone, enzalutamide, and radium-223. Starting in 2010, each of these agents was approved for prolonging life, and collectively, they altered the treatment paradigm of this disease. As a result, contemporary mCRPC trials that use OS as the primary end point capture the effects not only of the study drug during the clinical trial but also of between one and six other drugs administered in various permutations after the protocol-dictated treatment has been completed. The ELM-PC 5 trial may have fallen victim to this phenomenon, because the drug had to overcome an OS hurdle to successfully demonstrate a survival benefit. Orteronel is a CYP17 inhibitor with a mechanism of action similar, although not identical, to that of abiraterone. The trial design paralleled that of the pivotal trial of abiraterone acetate—COU-AA-301 (NCT00638690)—in that men were randomly assigned at a 2:1 ratio to receive either the drug with prednisone or placebo with prednisone, with OS as the primary end point. However, unlike COU-AA-301, the trial opened at a time when patients had access to postprotocol therapies, the most important of which was in fact therapy with abiraterone and prednisone. The ELM-PC 5 trial enrolled its first patient in November 2010, shortly after the US expanded-access program for abiraterone opened. In April 2011, in the midst of accrual to ELM-PC 5, abiraterone was approved in the United States. By the time of the last patient’s enrollment onto ELM-PC 5 in November 2012, abiraterone was available to patients treated in ELM-PC 5 at study sites in the United States, the European Union, Switzerland, Australia, Russia, and Brazil. Enzalutamide became available in the European Union and United States during the trial as well. Although patients in the placebo-plusprednisone arm received postprotocol therapy at roughly the same rate as those in the orteronel arm, because the opportunity to receive abiraterone off study grew, the trial became increasingly a test not of the hypothesis that CYP17 inhibition prolonged life compared with placebo, but rather of whether earlier exposure to a CYP17 inhibitor was superior to later treatment with a CYP17 inhibitor. Patients in Europe and North America had the highest rates of postplacebo use of CYP17 inhibitors, with 32% and 24% of patients, respectively, receiving abiraterone after the placebo-plus-prednisone treatment. Aptly, the authors point out that the trial was positive for OS outside Europe and North America, where postprotocol exposure to abiraterone was only 5% in the placebo-plus-prednisone arm. Indeed, if one compares the outcomes of ELM-PC 5 at these non–North American and non-European sites with those of COU-AA-301, the results are strikingly similar, as summarized in Table 1. These results at least prompt the question of whether this trial fell victim to timing; had it accrued before the rollout of abiraterone, would the results have been positive in Europe and North America, as they were in the rest of the world? An additional factor conspiring to reduce the apparent effectiveness of the drug was the short duration of treatment. Patients received a median of only 6.2 cycles of treatment during the study. No doubt toxicity may have had a role in the brevity of treatment; significant numbers of patients experienced nausea, vomiting, diarrhea, constipation, and other adverse events. However, another issue may have been at play. Unlike studies performed before 2010, the acceptance of maintaining patients in a placebo-controlled trial is significantly lower now that multiple life-prolonging treatment options are available, and this study likely reflects the end of placebo-controlled phase III clinical trial designs for the majority of men with mCRPC. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 7 MARCH 1 2015