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November 2016 Affiliated with Columbia University Medical Center and Weill Cornell Medicine
Early Chemotherapy Switch Shows Promise for Extending Survival in Advanced Prostate Cancer

There is a concerted effort underway at NewYork-Presbyterian/Weill Cornell Medical Center to pursue every opportunity to slow growth, even when a cancer cannot be eradicated.

This includes cases of metastatic castration-resistant prostate cancer (mCRPC), for which an effort to test a practical strategy to maximize the benefit from both of the approved taxanes—docetaxel and cabazitaxel (Jevtana; sanofi-aventis)—was joined by an effort to isolate a biomarker that tracks the activity of drugs in this class. Taxanes are the only class of chemotherapy associated with an overall survival benefit in mCRPC.

"On initial taxane about half of patients do not achieve a significant degree of PSA [prostate-specific antigen] decline," explained Scott T. Tagawa, MD, Medical Director of the Genitourinary Oncology Research Program at Weill Cornell Medicine.


"We also know that while the 2 approved taxanes are similar, they are not completely cross-resistant, meaning that tumors that develop resistance to 1 drug can respond to the other."

In a phase 2 trial he led and recently presented, patients who did not achieve an early robust response to 1 of the 2 approved taxanes were switched to the other.

In addition, all patients in this study, called TAXYNERGY (ClinicalTrials.gov Identifier: NCT01718353), were followed with a blood biomarker that is believed to track the mechanism by which taxanes slow disease progression. The biomarker is a quantification of androgen receptor (AR) translocation in circulating tumor cells (CTCs).

When patients who did not achieve a 30% or greater PSA decline by the fourth cycle of taxane were switched to the alternative agent, a higher proportion of patients than that reported historically reached the primary end point—a 50% or greater reduction in PSA. This level of PSA reduction has previously been associated with survival benefits in front-line chemotherapy. In addition, the improved response correlated with greater AR translocation, suggesting this is a mechanism of benefit.

Each of these findings represents a potential advance for the field, if further validated in the next set of studies. While cabazitaxel was approved after docetaxel and is considered the second-line option for taxane treatment, the study led by Dr. Tagawa not only suggests that some patients may respond better to one than the other available taxane, but also that the relative inhibition of AR trafficking into the nucleus of CTCs may explain why.

"TAXYNERGY is the first prospective trial to report AR nuclear localization in CTCs, and it demonstrates the feasibility of conducting a biomarker-rich trial across multiple sites," Dr. Tagawa said. The first stem cell transplant that affected sickle cell disease occurred in 1984 at the National Institutes of Health in a woman who underwent stem cell transplant for her leukemia. Serendipitously, she was also cured of her sickle cell disease. While stem cell transplant is the only cure available for sickle cell disease, few have been performed.

After 4 Cycles, a Switch

The study, which included centers in the United States and Canada, randomized 63 patients with mCRPC in a 2:1 fashion to 75 mg/m2 docetaxel or 25 mg/m2 cabazitaxel administered intravenously every 3 weeks. After 4 cycles of therapy, patients with less than a 30% reduction in PSA were switched to the alternative taxane. Those with a 30% or greater reduction remained on the initially assigned therapy.

"After a median of 14 months of follow-up, neither the median radiological progression-free survival nor the overall survival had been reached," said Dr. Tagawa, who presented these findings at the 2016 annual meeting of the American Society of Clinical Oncology (ASCO).

The precise mechanism of action of taxanes in mCRPC has been unclear, but previous work performed by Dr. Tagawa and others, including Paraskevi (Evi) Giannakakou, PhD, of Weill Cornell Medicine, has drawn attention to the inhibitory effect on AR trafficking. As part of TAXYNERGY, CTCs were monitored at baseline and intervals thereafter.

A circulating tumor cell with successful "drug-target engagement" with taxane chemotherapy. Left: Microtubules stained red are stabilized. Right: The androgen receptor stained green is unable to enter the nucleus in the center because the microtubules are stabilized by taxane chemotherapy.


The significant reduction in AR trafficking in responders is consistent with the hypothesis that taxanes slow progression by stabilizing microtubules to prevent AR translocation into the nucleus.

By both tracking a potential new treatment strategy and exploring a mechanism of action, the TAXYNERGY trial provides an example of the effort to advance clinically relevant research. Ultimately, the goal is to extend survival in patients with prostate cancer. By understanding the pathophysiology of advancing mCRPC and the strategies by which it is controlled, there is an opportunity to maximize the benefit of current options while laying the groundwork for exploring new options.

"With the relatively recent evidence that taxanes can also slow progression of metastatic hormone-sensitive prostate cancer, there is an even greater urgency for understanding the mechanism of action," Dr. Tagawa said. The work he is leading suggests that the cytotoxic effects of taxanes may not be the sole or even the most important source of antitumor activity. This work is consistent with other initiatives that Dr. Tagawa has been leading in the search for viable biomarkers that will yield more logical and systematic approaches in the pursuit of cancer control.

 
   
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