Phase 3 Clinical Trial Results for TAK-700 - Metastatic, Hormone Sensitive

This phase 3 clinical trial (SWOG 1216) included 1300 patients with newly diagnosed metastatic castration-sensitive prostate cancer that were randomized to androgen deprivation therapy plus bicalutamide, versus androgen deprivation therapy plus TAK-700.

They say that this trial did not meet the “statistical significance” and didn’t meet the primary endpoint for overall survival, but check these results and video out.

- The median overall survival in the control arm with ADT plus bicalutamide was 70 months. The median overall survival in the experimental arm was 81 months. So there was an 11-month improvement in median overall survival in the experimental arm, with a p-value of 0.040 and a hazard ratio of 0.86, favoring TAK-700. (11 months…I find that very interesting….)

- The progression-free survival was remarkably improved, in fact, it doubled with TAK-700. The median PFS in the control arm was 23 months and the median PFS in the experimental arm with TAK-700 was 47.6 months with a hazard ratio of 0.56 and a p-value of less than 0.001. Even PSA response rates were also significantly higher.

The below article and video talk about this trial and seem to suggest that results might be even better with some of the newer hormone therapy drugs like Zytiga used in combination with TAK-700. (I’m not sure about Xtandi, but would be interesting if this could be a possible combination….).

https://www.urotoday.com/categories-media/2013-centers-of-excellence/mhspc-coe/2215-the-addition-of-tak-700-to-testosterone-suppression-its-effect-on-survival-in-mcspc-swog-1216-neeraj-agarwal.html

<< What this shows is that collectively the available home therapy intensification drugs and chemo approaches are working quite well in extending lives for these mHSPC guys. We think if the standard of care today, with modern multiple hormone intensification strategies, was in use in 2012, these patients could have exceeded 9-10 years OS. >>

I like the sound of that! Obviously not for the guys who missed it in 2012, but for those of us currently on that treatment strategy.

Jerry,
First I totally agree with gratitude to all participants in clinical trials. I remember when Sonny and a few other guys I have associated with that were on this trial. Of course all I could do is cheer them on because the purpose of any clinical trial is to answer a question and we had not had these questions answered yet with TAK700.

I brief history of TAK700 in prostate cancer. Dating years back before even we had docetaxel (TAX327 Trial in 2004) we had several potential drugs in regular use. One such drug was Ketocanazole, or Keto for short. Keto worked to some degree by inhibiting the enzymes CYP17,20. The down side of Keto is that it destroyed livers. Researchers looked for better ways to attack this pathway and eventually in 2009 abiraterone acetate cleared with expedited release as a well working Cyp17, 20 inhibitor. It extended lived. On the down side of the drug is the requirement for a corticosteroid. Prednisone. TAK700 was being researched in Japan and could be seen as an alternative to abiraterone. Here is a breakdown of this research:

https://www.ncbi.nlm.nih.gov/pmc/articles/pmc3047603/

TAK700 had failed in demonstrating improved survival in mCRPC patients in previous trials. It was questionable if is would work in the mHSPC setting. Enter S1216. However after these trials all failed, I see a likely end to TAK700 after S1216 for use in prostate cancer.

The STAMPEDE trial showed that abiraterone worked in the mHSPC setting but it came with the need for a steroid. If TAK700 could show a 25% improvement in S1216 in OS in S1216 it would be a reasonable alternative to Zytiga. It did not do so. Thus it was not considered a success. As it is, it was still a great trial that gave us great information. That's what a long and drawn out trial with good design can do even if the experimental drug does not make its endpoints.

Considering the ties between abiraterone and TAK700 both being CYP17,20 attack mechanisms, It is not likely that they could be used together to improve the results. This is one of the Exclusion Criteria of S1216 was:

"Prior or concurrent therapy with ketoconazole, aminoglutethimide or abiraterone acetate, or enzalutamide (MDV3100)."

Simply put these AR drugs would contaminated our trial. And in the end they were disallowed unless progression indicated allowing their use.

Tony

Post Edited (Tony Crispino) : 7/4/2021 4:35:32 PM (GMT-6)

mattam,
When this trial began, the trial had flexibility in the use of changing standard of care. There were a lot of trials and treatment options added after S1216 got launched. This includes early intervention trials for docetaxel (CHAARTED), early use of abiraterone (STAMPEDE) and many new agents driven by, but not just driven by, 2nd line hormonal therapies. We've seen new target agents for PD1/PDL1, BRCA, CHEK2, ATM, and even targeting with Lu177 PSMA. What I indicate is that the median was 70 months in the trial for the SOC side which kept improving during the life of this trial. So is it possible that we can see todays standard of care showing in a new Phase III trial a potential median of 9-10 years. Yes I think that's possible. Maybe probable.

Jerry, here is the Phase III results and final reporting on the Titan trial that tested in the same scenario as the TAK-700 trial. mHSPC and mCSPC are the same patients. As you can see TAK-700 had no where near the positive results that apalutamide did. I expect with this reporting I'll see some email coming from another direction through the AUA/ASTRO/SUO advanced prostate cancer guideline panel that we'll agree to recommend lupron and apalutamide to be considered in the care for these mHSPC patients.

https://ascopubs.org/doi/abs/10.1200/jco.20.03488

Exactly my question, Jerry. Hope, I picked a good one! 😉

Yes Jerry,
I think the shifting of combinations 1st and 2nd line ADT drugs have significantly increased survival by years instead of a just a few months. Plus, throw in Chemo -- that's a lot combinations and permutations. I really hope some non-ADT breakthroughs come soon. Maybe mRNA therapies will help us out.