Jevtana [Cabazitaxel] & Androgen Status.

[pjoshea13]

New Dutch study below.

Jevtana is a taxane (as is Taxotere), & was approved by the FDA for men with CRPC in 2010.

Typically, in castrate-resistant PCa [CRPC], the cancer remains androgen-sensitive & has found alternative sources. For instance, there is a potential pathway that produces DHT (dihydrotestosterone) but not via the usual T (testosterone) path. Also, PCa cells accumulate cholesterol, which potentially can be used to produce any of the steroid hormones. And cholesterol itself can be synthesized within PCa cells, if circulating cholesterol - particularly VLDL-C - is too low to meet the demand. The important thing is that the androgen receptor [AR] continues to be relevant in most CRPC.

In the new study, Jevtana was found to be less effective in the presence of T. Doubtless, they would have found the same with DHT.

It is not a human study, but did use a "clinically relevant patient-derived xenograft model of castration resistant disease".

"We found that cabazitaxel is highly effective in a castrate setting with strongly reduced AR activation, while tumor growth inhibition by cabazitaxel was completely abolished in the presence of high AR pathway activity.

"Moreover, additional experiments showed that intratumoral cabazitaxel levels were 3.5 times higher in tumors from castrated mice as compared to tumors from androgen-supplemented animals."

So the problem is uptake.

How can one improve efficacy of Jevtana in CRPC? (a) Avodart will block DHT production. (b) A statin such as Simvastatin might reduce cholesterol uptake. (c) The statin would also inhibit the creation of cholesterol. (d) An antiandrogen such as Casodex of Xtandi, if not resistant, will inhibit AR activity. (e) Zytiga, if not resistant, will prevent the conversion of pregnenolone and progesterone to androgens.

-Patrick

ncbi.nlm.nih.gov/pubmed/292...

EBioMedicine. 2017 Dec 20. pii: S2352-3964(17)30505-4. doi: 10.1016/j.ebiom.2017.12.024. [Epub ahead of print]

Testosterone Diminishes Cabazitaxel Efficacy and Intratumoral Accumulation in a Prostate Cancer Xenograft Model.

Mout L1, de Wit R2, Stuurman D3, Verhoef E4, Mathijssen R1, de Ridder C3, Lolkema M1, van Weerden W3.

Author information

1

Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.

2

Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. Electronic address: [e-mail].

3

Department of Experimental Urology, Erasmus University Medical Centre, Rotterdam, The Netherlands.

4

Department of Pathology, Erasmus University Medical Centre, Rotterdam, The Netherlands.

Abstract

Inactivation of the androgen receptor (AR) pathway by androgen deprivation therapy (ADT) is the mainstay of (metastatic) prostate cancer therapy. Ultimately, the AR pathway will be re-activated despite castrate levels of circulating androgens. Thereby, maintaining its role even in castration resistant prostate cancer (CRPC). The recent STAMPEDE and CHAARTED trials showed that docetaxel in combination with ADT increased survival in hormone sensitive prostate cancer patients, suggesting cross-talk between AR signaling and chemotherapy efficacy. We hypothesized that a similar interaction may also apply for CRPC that is treated with cabazitaxel. We studied the impact of androgen status on the efficacy, pharmacodynamics and -kinetics of cabazitaxel in a unique and clinically relevant patient derived xenograft model of castration resistant disease. We found that cabazitaxel is highly effective in a castrate setting with strongly reduced AR activation, while tumor growth inhibition by cabazitaxel was completely abolished in the presence of high AR pathway activity. Moreover, additional experiments showed that intratumoral cabazitaxel levels were 3.5 times higher in tumors from castrated mice as compared to tumors from androgen-supplemented animals. We confirmed that cabazitaxel pharmacokinetics were not affected by testosterone, suggesting that androgen status might influence cabazitaxel tumor uptake directly. This study reveals the impact of androgen status on cabazitaxel efficacy and supports the potential of combination of taxane chemotherapeutics with AR axis targeting agents.

KEYWORDS:

Androgen receptor; Cabazitaxel; Castration resistant prostate cancer; Pharmacodynamics; Pharmacokinetics; Testosterone

PMID: 29276148 DOI: 10.1016/j.ebiom.2017.12.024

[BigRich]

I read that 325,000 people with irregular heartbeat have a deadly cardio vascular event every year. I have an irregular heartbeat. Why wife maybe right that PCa is not going to kill me. I have kidney disease and 14% die from this cause. I haven't even addressed diabetes deaths. I have diabetes.

So that, I will probably die with PCa, and not from it.

Rich

[Hidden in reply to BigRich]

Is that irregular heartbeat atrial fibrillation? That's what I have. There are medication and surgical options for that; I am on meds. There are fancy, and no doubt expensive, blood thinner meds to guard against the risk of stroke. I just take a low dose aspirin daily. My a-fib is well controlled.

[BigRich in reply to Hidden]

I take a 325 mg aspirin daily.

Rich

[Sisira]

The best part of this post is the 5 ways of improving the efficacy of Jevtana in CRPC. It very clearly forms a multi prong strategy to prevent the cancer from progressing at a very advanced stage.

Thank you Patrick for the much simplified explanation.

Wish you a Happy New Year!

Sisira

[BigRich]

Patrick, Thank you for increasing my knowledge base.

Rich