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Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer

pjoshea13 profile image
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New study below [1] (full text).

"The efficacy and safety of cabazitaxel, as compared with an androgen-signaling–targeted inhibitor (abiraterone or enzalutamide), in patients with metastatic castration-resistant prostate cancer who were previously treated with docetaxel and had progression within 12 months while receiving the alternative inhibitor (abiraterone or enzalutamide) are unclear."

"Cabazitaxel significantly improved a number of clinical outcomes, as compared with the androgen-signaling–targeted inhibitor (abiraterone or enzalutamide), in patients with metastatic castration-resistant prostate cancer who had been previously treated with docetaxel and the alternative androgen-signaling–targeted agent (abiraterone or enzalutamide). (Funded by Sanofi; CARD ClinicalTrials.gov number, NCT02485691. opens in new tab.)"

"Our trial results prospectively confirm that patients with metastatic castration-resistant prostate cancer who had previously been treated with docetaxel and had disease progression within 12 months while receiving an androgen-signaling–targeted inhibitor (abiraterone or enzalutamide) had longer imaging-based progression-free survival and overall survival when treated with cabazitaxel than when treated with the other androgen-signaling–targeted inhibitor (abiraterone in patients who had previously received enzalutamide, or enzalutamide in those who had previously received abiraterone). Cabazitaxel more than doubled the imaging-based progression-free survival (median, 8.0 months vs. 3.7 months with an androgen-signaling–targeted inhibitor), and this benefit was observed across all the prespecified subgroups, regardless of the timing of the previous alternative androgen-signaling–targeted inhibitor therapy (before or after docetaxel). Cabazitaxel resulted in a risk of death from any cause that was 36% lower than that with abiraterone or enzalutamide, despite 33% of the patients in the androgen-signaling–targeted inhibitor group crossing over to receive cabazitaxel at the time of progression. All key secondary end points (overall survival, progression-free survival, PSA response, and tumor response) also favored cabazitaxel.

The results of the CARD trial are in agreement with those of previous studies that have shown poor outcomes with a second androgen-signaling–targeted inhibitor.22-25 This is probably due to the fact that these agents target the same pathway and thus share common mechanisms of resistance. Conversely, taxanes, owing to their different mechanism of action, are able to overcome several mechanisms of resistance to androgen-signaling–targeted inhibitors, such as increased androgen-receptor signaling and PTEN (phosphatase and tensin homologue) loss.29-33 In addition, although some studies suggest that docetaxel loses some activity in tumors that are resistant to androgen-signaling–targeted inhibitors, prospective and retrospective data show that cabazitaxel retains its activity in this context.18,19,26,34,35 This may be attributed to greater intratumoral penetration with cabazitaxel than with docetaxel, especially in treatment-resistant tumors.36,37

The incidence of adverse events of grade 3 or higher was similar in the two treatment groups (56.3% with cabazitaxel and 52.4% with an androgen-signaling–targeted inhibitor). The incidence of adverse events leading to death during the trial was twice as high with an androgen-signaling–targeted inhibitor as with cabazitaxel; this finding was mainly related to disease progression. Neutropenic complications with cabazitaxel usually occur at cycle 1, especially when the baseline neutrophil count is below 4000 per cubic millimeter.38 Therefore, all patients in the cabazitaxel group received prophylactic granulocyte colony-stimulating factor during every cycle in the trial. With granulocyte colony-stimulating factor, the incidence of febrile neutropenia of grade 3 or higher that was observed in this trial (3.2%) was similar to that observed in the AFFINITY phase 3 trial (3%), which also allowed the use of prophylactic granulocyte colony-stimulating factor from cycle 1, with 59% of the patients having received both docetaxel and an androgen-signaling–targeted inhibitor.39

This was an open-label trial with no central review of the standard imaging, although a previous study has suggested little variance between local and central imaging review in this population.40 Moreover, results regarding multiple secondary end points, including overall survival, in this trial were significant in favor of cabazitaxel. Second, the cabazitaxel starting dose of 20 mg per square meter was not tested. In the prospective, noninferiority, phase 3 trial PROSELICA, a dose of 20 mg per square meter maintained at least 50% of the survival benefit of a dose of 25 mg per square meter (which had been compared with mitoxantrone in the TROPIC trial) and was associated with a lower incidence of adverse events of grade 3 or higher.4,20 For the CARD trial, we used a dose of 25 mg per square meter because the trial was conducted in Europe and the European label was used as a reference. The incidence of febrile neutropenia with the cabazitaxel dose of 25 mg per square meter was lower in the CARD trial (3.2%) than in TROPIC (8%) and PROSELICA (9.2%), probably owing to the use of prophylactic granulocyte colony-stimulating factor from cycle 1.4,20

No preplanned analysis of the influence of the sequence of abiraterone–enzalutamide (or vice versa) was undertaken. However, since retrospective studies suggest that the sequence of androgen-signaling–targeted inhibitors may influence progression-free survival, post hoc analyses were performed, which confirmed the superiority of cabazitaxel over the androgen-signaling–targeted inhibitor regardless of whether abiraterone or enzalutamide was received during the trial.41-44

In conclusion, cabazitaxel led to longer imaging-based progression-free survival than abiraterone or enzalutamide among patients with metastatic castration-resistant prostate cancer who had previously received docetaxel and the alternative androgen-signaling–targeted inhibitor (abiraterone or enzalutamide). Cabazitaxel also significantly improved overall survival and other secondary end points."

-Patrick

[1] nejm.org/doi/full/10.1056/N...

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cesces profile image
cesces

Dumb question.

Is Cabazitaxel considered a chromo drug or an androgen drug?

pjoshea13 profile image
pjoshea13 in reply to cesces

Cabazitaxel [Jetvana] is a taxane, as is the the more familiar Docetaxel [Taxotere]. This class of chemotherapy drug has names ending in "taxel".

Cabazitaxel does not target the androgen receptor axis (as does Abi & Enza).

-Patrick

cesanon profile image
cesanon in reply to pjoshea13

Patrick,

I found the following on Wikipedia. Am I reading it properly to indicate that it does have some androgen receptor activity?

en.wikipedia.org/wiki/Cabaz...

"Taxanes enhance the microtubules stabilization and inhibit the cellular mitosis and division.[3] Moreover, taxanes prevent androgen receptor (AR) signaling by binding cellular microtubules and the microtubule-associated motor protein dynein, thus averting AR nuclear translocation.[4]"

[4] Darshan, M. S.; Loftus, M. S.; Thadani-Mulero, M.; Levy, B. P.; Escuin, D.; Zhou, X. K.; Gjyrezi, A.; Chanel-Vos, C.; Shen, R. (2011-09-15). "Taxane-Induced Blockade to Nuclear Accumulation of the Androgen Receptor Predicts Clinical Responses in Metastatic Prostate Cancer". Cancer Research. 71 (18): 6019–6029. doi:10.1158/0008-5472.CAN-11-1417. ISSN 0008-5472. PMC 3354631.

GP24 profile image
GP24 in reply to cesanon

If it averts AR nuclear translocation it has androgen receptor activity. Xtandi averts nuclear translocation too, among other effects.

cesanon profile image
cesanon in reply to GP24

LOL.... is that a yes to my question?

pjoshea13 profile image
pjoshea13 in reply to cesanon

Fair enough ...

but the primary mechanism is described as induction of:

"... microtubule stabilization, mitotic arrest, and apoptotic cell death ..."

From the "new" finding (2011):

"Here, we report that taxanes inhibit ligand-induced AR nuclear translocation and downstream transcriptional activation of AR target genes such as prostate-specific antigen. AR nuclear translocation was not inhibited in cells with acquired β-tubulin mutations that prevent taxane-induced microtubule stabilization, confirming a role for microtubules in AR trafficking."

Drugs that "target the androgen receptor axis" are generally taken to be those that inhibit the availability of androgens + those that compete for binding to the androgen receptor [AR]. So that would not include taxanes.

I can think of a couple of other possibilities - anything that limits the "expression" of AR (ie. the number of occurrences), & anything that accelerates the clearance of AR - but usage in PubMed seems currently limited to classic & extended ADT + AR antagonists.

Turns out that the question wasn't so simple. LOL

-Patrick

cesanon profile image
cesanon in reply to pjoshea13

Is there any reason to believe that its androgen receptor activity is a material or major component of its effectiveness.

MateoBeach profile image
MateoBeach

Thank you for sharing this important result in expanded form. It is certainly useful in guiding sequencing decisions in advanced prostate cancer management.

dockam profile image
dockam

Thanks for that post. I may be castrate resistant with PSA @ 6.7 whilst on ADT from 12/18. Axumin scan on 10/21 with Kaiser and wanted to advocate for another course of chemo (did 15 Taxotere sessions in 2015) than abiraterone or enzalutamide. But, I'll make my 5 yr point with PSA @ 555.2 on 10/13/2014

My best to you all on your Journey (Camino)

Fight on

Randy

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