Takeda Pharmaceutical Co. has unblinded the Phase III clinical trial of ortoronel + prednisone in treatment of men with progressive, metastatic, castration-resistant prostate cancer (mCRPC) who had been previously treated with at least one cycle of docetaxel-based chemotherapy. Apparently ortoronel + prednisone was not going to demonstrate the necessary, pre-specified level of clinical efficacy in this group of patients.
Based on a media release issued by Takeda Pharmaceutical Co. late yesterday, The “New” Prostate Cancer InfoLink understands that this trial was unblinded after a scheduled interim analysis by the data monitoring committee “indicated that orteronel + prednisone would likely not meet the primary endpoint of improved overall survival (OS) when compared to the control arm (HR 0.894, p = 0.226).”
Apparently this interim analysis did, however,
- Show an advantage for patients in the orteronel + prednisone arm of the trial for the secondary endpoint of radiographic progression-free survival (rPFS) compared to the patients treated with a placebo + predisone in the control arm of the study (HR = 0.755, p = 0.00029).
- Indicate no significant safety concerns associated with treatment with ortoronel + prednisone.
Takeda is allowing all patients who were randomized to orteronel + prednisone in this trial (referred to by Takeda as the ELM-PC 5 study) to continue on therapy after appropriate consultation with their physicians and study investigators (if they wish to do this).
Takeda also notes that the company’s decision to unblind the ELM-PC 5 study is not expected to impact other, ongoing, company-sponsored clinical trials with orteronel, including the pivotal Phase III study of orteronel + prednisone vs. a placebo + prednisone in men with chemotherapy-naive mCRPC (referred to by Takeda as the ELM-PC 4 study).
The company has announced that detailed safety and efficacy findings from this trial will be presented at an appropriate forum as soon as they have been prepared and analyzed. The “New” Prostate Cancer InfoLink suspects that it would probably be possible to conduct such an analysis in time to present data at the Genitourinary Cancers meeting in San Francisco next January, although we don’t know if Takeda will try to meet that goal.
Clearly the failure of ortoronel to show a survival benefit in post-chemotherapy patients with mCRPC will be a disappointment to many. However, the fact that there were no unexpected, serious side effects associated with this Phase III trial does leave the door open to the possibility that the drug will show efficacy in men with earlier-stage prostate cancer.
The media release quotes Dr. Michael Vasconcelles, the global head of the Takeda Oncology Therapeutic Area Unit as stating that:
While we are disappointed that the ELM-PC 5 study did not meet the primary endpoint of improved overall survival, we remain committed to developing new therapies for patients with prostate cancer. We would like to acknowledge with gratitude the patients, their families, and the study investigators for their significant contributions to the ELM-PC 5 trial. Takeda remains dedicated to developing innovative treatment options for patients with cancer.
Filed under: Drugs in development, Living with Prostate Cancer, Management, Treatment | Tagged: castration-resistant, mCRPC, metastatic, ortoronel, post-chemotherapy, TAK-700 |
THE "NEW" PROSTATE CANCER INFOLINK 
Speaking as a patient advocate at, and on behalf of SWOG, after I saw this release I took this back into the GU committee to discuss as I am currently working on a TAK-700 trial as one of the protocol team members. I have seen a few posts in online communities that this media release indicates the “end of the line” for orteronel. I stress to this community that is far from the case. Please review our response:
“Although I agree that ELM-PC5 study did not show improved overall survival (OS), it does not mean orteronel (TAK-700) did not show clinical efficacy. The progression-free survival (PFS) endpoint (meaning how good orteronel was in delaying disease progression) very significantly favored Orteronel (HR = 0.755, p = 0.00029). This does tells us that orteronel is an effective lyase inhibitor and delays disease progression in prostate cancer by blocking androgen synthesis by prostate cancer cells. In addition to establishing clinical efficacy of orteronel as delaying disease progression, ELM-PC5 trial also established Orteronel as a very safe drug.
“So, the question arises why orteronel did not improve OS. This is very much possible because of the fact that the patients who progressed on placebo on ELM-PC5 later benefited from treatment with Zytiga (which has a similar mechanism of action) which became available by prescription due to FDA approval in the middle of ELM-PC5 trial. Post-ELM-PC5 treatment with Zytiga possibly blurred (confounded) the effect of orteronel on OS in this trial.
“This likely will have impact on other similar androgen synthesis inhibitors which are currently in trials. Remember, Zytiga in pre-chemo trial also did not show an OS benefit but did show improved PFS, likely because these patients had other treatments available after progressing on that trial.
“There are other clinical trials of orteronel ongoing, which include those in the pre-chemotherapy, non-metastatic setting as well as in newly diagnosed metastatic prostate cancer patients (S1216, clinicaltrials.gov: NCT01809691, funded by National Cancer Institute), who have not yet developed resistance to androgen deprivation therapy (like Lupron). Advantages of enrolling in those trials include receiving an androgen synthesis blocker (orteronel), which is potent, safe, and free. In some of these trials, including S1216, orteronel is given without prednisone. Given results of ELM-PC5 trial, it is very likely that orteronel will delay disease progression in these settings as well.”
Currently there are five TAK-700-related trials still active and this press release does not apply to them. I want to encourage all patients to continue to strongly consider these trials as one of their options. Both TAK-700 and abiraterone acetate are CYP-17,20-lyase inhibitors, but the need for a better version still exists. I believe that TAK-700 will be a great option for men pre- and post-metastatic detection into the future.