Promising study shows prostate cancer circulating tumour cells could be used as surrogate for survival, speeding drug testing and approvals

An analysis of a prospective, randomized Phase III trial showing the effectiveness of a drug in extending overall survival in metastatic castration-resistant prostate cancer (mCRPC) also has found that the level of circulating tumour cells (CTCs) – cancer cells that have broken off from the tumour and into the bloodstream – correlated with survival.

These initial results have led to the investigation of the use of CTCs as part of a biomarker panel for survival in clinical trials for castration-resistant disease.

A problem plaguing the prostate cancer field is the identification of reliable early indicators that a drug can prolong life. Such indicators, or surrogates, can be used in lieu of a survival endpoint in clinical trials, allowing drugs to be tested in smaller, less costly trials that could potentially enable faster approvals by the U.S. Food and Drug Administration. Changes in prostate specific antigen (PSA) have not been shown to be surrogates for survival in prospective trials and cannot be used for regulatory approvals.

In the Phase III COU-AA-301 trial, a study of 1,195 patients showed that the drug abiraterone acetate (Zytiga) significantly improved overall survival in mCRPC (15.8 months for those on abiraterone and prednisone versus 11.2 months for those on prednisone and placebo). In this trial, investigators evaluated CTC counts in 972 patients at baseline, and in 723 patients after three months, finding that the abiraterone therapy reduced the number of CTCs, "converting" them from unfavorable (CTC greater than or equal to five) to favorable (CTC less than five) counts. This was predictive of a better prognosis and overall survival as early as four weeks after treatment.

According to lead author Howard I. Scher, MD, the D. Wayne Calloway Chair in Urologic Oncology and chief of the Genitourinary Oncology Service at Memorial Sloan-Kettering Cancer Center in New York, studies have linked declining numbers of CTCs with improved overall survival in mCRPC, and in some cases, have been shown to be a more powerful early predictor of survival than PSA among men with prostate cancer.

"The ultimate goal of these studies is to develop a biomarker panel that includes CTCs that can be used in Phase III trials instead of a survival endpoint," said Dr. Scher. "This trial was the first to show a survival benefit with the CTC question embedded, and which is part of a formal collaboration with the FDA. Preliminary results show that CTC and lactate dehydrogenase (LDH) are prognostic, confirming previous studies. This trial becomes the basis for a biomarker panel that we will create, which will then be tested prospectively in subsequent trials. To establish a surrogate for survival is a multistep process that requires consistent results in multiple Phase III studies and which have the CTC biomarker question embedded. Our results are very encouraging for the use of CTCs."

Dr. Scher added that while favorable changes in CTC are associated with a better prognosis, the results cannot be used alone to guide treatment decisions for an individual patient. Testing whether changes in CTC can be used to manage individual patients "will require a new, dedicated trial that specifically asks this question."

The researchers are continuing their work to define a biomarker panel that is most strongly associated with overall survival in mCRPC.


Source: ASCO

Reference: ASCO 2011 Abstract: LBA4517 Evaluation of circulating tumour cell (CTCs) enumeration as an efficacy response biomarker of overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC): Planned final analysis (FA) of COU-AA-301, a randomized, double-blind, placebo-controlled, phase III study of abiraterone acetate (AA) plus low-dose prednisone (P) post docetaxel. H. I. Scher, G. Heller, A. Molina, T. S. Kheoh, G. Attard, J. Moreira, S. K. Sandhu, C. Parker, C. Logothetis, R. T. McCormack, K. Fizazi, A. Anand, D. C. Danila, M. Fleisher, D. Olmos, C. M. Haqq, J. S. De Bono.