Orteronel (TAK-700) fails in Advanced Prostate Cancer

Several comments to the above post. Glucocorticoids such as prednisone and dexamethasone have been shown to lower PSA in CRPC patients presumably because, like a CYP17 lyase inhibitor, they suppress adrenal androgens. Prednisone is therefore not an ‘inactive’ placebo.
Orteronel did prolong the rPFS end-point but not overall survival. It is likely that the patients whose cancer progressed in either study arm were put on Xtandi or Zytiga and therefore had an improved survival outcome. The ‘crossover’ to newly approved effective agents likely confounded the OS results. Therefore, we will not know from this trial whether there would be a survival advantage to orteronel plus prednisone compared to prednisone alone. The crossover phenomenon (to Zytiga predominantly) has also reportedly delayed the interpretation of OS results in the Xtandi pre-chemo patient study and is impacting analyses of several current Ph 3 studies.
It was not the lack of potency of orteronel that resulted in the failure to meet the OS end-point but rather the complex regulatory/development environment that provided new effective therapies that patients could transition to while on study. Human genetics and phenotype analyses tells us that a ‘clean’ CYP17 lyase inhibitor should be as effective at reducing adrenal and tumor androgens as a ‘dirty’ combined CYP17 lyase plus hydroxylase inhibitor. A clean lyase inhibitor would not require prednisone and theoretically should be even more efficacious in the treatment of CRPC since, unlike Zytiga it would not cause the accumulation of upstream steroids such as progesterone or pregnenolone that – like prednisone or dexamethasone – can activate the mutated androgen receptors present in CRPC patients.
Chief Scientific Officer
Viamet Pharmaceuticals

Bill, many thanks for your considered comments. You make some good points, some of which I had already mentioned to those who subscribe to my email blog alerts.

I agree with you that the orteronel efficacy data could have been confounded by those on the placebo arm crossing over on progression to other active treatments such as cabazitaxel and later enzalutamide when it was approved.

This does result in an increased risk that the placebo arm could actually receive more treatment than the orteronel arm, especially when those on placebo are likely to progress earlier. So there is a possibility that the orteronel efficacy could have been confounded and I am sure we will hear more about this when the results are presented.

That said, all the other drugs that have been approved in the post-chemo CRPC space have shown a significant overall survival advantage. Without that I don’t think orteronel can possibly compete. I can’t see it being approved for post-chemo CRPC based on rPFS when abiraterone, enzalutamide, radium-223 and cabizataxel have all shown a significant overall survival advantage.

The bottom line: if orteronel is not approved for post-chemo CRPC, which I think is most unlikely without OS, then it’s an expensive commercial failure in that space. Lack of OS efficacy in post chemo also does not bode well for the pre-chemo setting given even more options are available to patients later, including docetaxel.

The challenge for any drug that is 3rd or more to market is in demonstrating superior efficacy or an improved value proposition over the competition. None appear to exist here.

Thanks again for sharing your thoughts. Pieter

2 Responses to “Orteronel (TAK-700) fails in Advanced Prostate Cancer”

Bill Moore July 31, 2013

Several comments to the above post. Glucocorticoids such as prednisone and dexamethasone have been shown to lower PSA in CRPC patients presumably because, like a CYP17 lyase inhibitor, they suppress adrenal androgens. Prednisone is therefore not an ‘inactive’ placebo.
Orteronel did prolong the rPFS end-point but not overall survival. It is likely that the patients whose cancer progressed in either study arm were put on Xtandi or Zytiga and therefore had an improved survival outcome. The ‘crossover’ to newly approved effective agents likely confounded the OS results. Therefore, we will not know from this trial whether there would be a survival advantage to orteronel plus prednisone compared to prednisone alone. The crossover phenomenon (to Zytiga predominantly) has also reportedly delayed the interpretation of OS results in the Xtandi pre-chemo patient study and is impacting analyses of several current Ph 3 studies.
It was not the lack of potency of orteronel that resulted in the failure to meet the OS end-point but rather the complex regulatory/development environment that provided new effective therapies that patients could transition to while on study. Human genetics and phenotype analyses tells us that a ‘clean’ CYP17 lyase inhibitor should be as effective at reducing adrenal and tumor androgens as a ‘dirty’ combined CYP17 lyase plus hydroxylase inhibitor. A clean lyase inhibitor would not require prednisone and theoretically should be even more efficacious in the treatment of CRPC since, unlike Zytiga it would not cause the accumulation of upstream steroids such as progesterone or pregnenolone that – like prednisone or dexamethasone – can activate the mutated androgen receptors present in CRPC patients.
Chief Scientific Officer
Viamet Pharmaceuticals

3NT July 31, 2013

Bill, many thanks for your considered comments. You make some good points, some of which I had already mentioned to those who subscribe to my email blog alerts.

I agree with you that the orteronel efficacy data could have been confounded by those on the placebo arm crossing over on progression to other active treatments such as cabazitaxel and later enzalutamide when it was approved.

This does result in an increased risk that the placebo arm could actually receive more treatment than the orteronel arm, especially when those on placebo are likely to progress earlier. So there is a possibility that the orteronel efficacy could have been confounded and I am sure we will hear more about this when the results are presented.

That said, all the other drugs that have been approved in the post-chemo CRPC space have shown a significant overall survival advantage. Without that I don’t think orteronel can possibly compete. I can’t see it being approved for post-chemo CRPC based on rPFS when abiraterone, enzalutamide, radium-223 and cabizataxel have all shown a significant overall survival advantage.

The bottom line: if orteronel is not approved for post-chemo CRPC, which I think is most unlikely without OS, then it’s an expensive commercial failure in that space. Lack of OS efficacy in post chemo also does not bode well for the pre-chemo setting given even more options are available to patients later, including docetaxel.

The challenge for any drug that is 3rd or more to market is in demonstrating superior efficacy or an improved value proposition over the competition. None appear to exist here.

Thanks again for sharing your thoughts. Pieter

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Orteronel (TAK-700) fails in Advanced Prostate Cancer

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Posted by Pieter Droppert

2 Responses to “Orteronel (TAK-700) fails in Advanced Prostate Cancer”