Last year after the ASCO meeting in Chicago I declared that there was one particular presentation of the CHAARTED trial that would be a game changer for the treatment of newly diagnosed men with very significant prostate cancer. The game changer was that men diagnosed with significant disease and who were still ADT naive (not yet had any hormone therapy) would have their life extended if they had a short course (six sessions) of chemotherapy despite their still being hormone sensitive.
As happens in scientific research this finding was contradicted at one of last month’s plenary session at ASCO GU. At the session Dr. Gwenaelle Gravis, MD, PhD from the Department of Medical Oncology, Institute Paoli Calmettes in France reported on the long-term results of the phase III androgen deprivation therapy (ADT) plus docetaxel (D) versus ADT alone for hormone-naïve metastatic prostate cancer (mPCa) (trial known as GETUG 15).
In this trial 385 men with metastatic prostate cancer were randomized to receive ADT+D vs ADT. The initial analysis was published in the Lancet Oncology in 2013 (http://www.ncbi.nlm.nih.gov/pubmed/23306100). At the ASCU GU conference Dr. Gravis presented an updated analysis which included a retrospectively reviewe of the subjects to stratify them into high-volume (HVD) vs low-volume (LVD) disease to allow for a more accurate comparison with the CHAARTED trial.
Just like in the CHAARTED trial significant disease was defined as visceral metastases and/or four or more bone metastases with at least one beyond the pelvis and the vertebral column.
Upon analysis Dr. Gravis concluded that her data indicated that the “addition of docetaxel to ADT did not significantly improve overall survival (OS) in men with hormone-naïve metastatic prostate cancer. In her retrospective analysis using the newly aligned definition of volume of metastasis as in CHAARTED there was a non-significant 4 months increase in OS with ADT+D.”
These findings run in conflict with the Sweeney et al’s plenary session at ASCO in May 2014 (reporting the results of the ECOG 3805 Phase III Randomized Study of Chemohormonal Therapy Versus Androgen Ablation Therapy in Patients With Extensive Metastatic Prostate Cancer [CHAARTED] trial.
In the CHAARTED trial, 790 men with hormone-sensitive metastatic prostate cancer (HS-mPCa) were randomized to receive androgen-deprivation therapy (ADT) alone or ADT in addition to docetaxel (D).
It concluded that in men with high-volume disease (visceral metastases and/or four or more bone metastases) the overall survival was significant higher in the ADT+D cohort (49.2 months) than in the ADT alone group (32.2 months). These results achieved statistical significance (HR 0.60; 95% CI 0.45-0.81; p=0.0006) thus leading many to advocate the use of combined ADT+D in patients with newly diagnosed HS-mPCa.
Following Dr Gravis’s presentation Dr. Eric Small from UCSF and Dr. Evan Yu of the University of Washington lead a discussion and comparison of CHAARTED and GETUG 15 in an attempt to reconcile the seemingly contradictory conclusions. They argued that there were significantly more men in the CHAARTED trial thus it was better powered compared to GETUG 15 to assess for an OS difference between the two groups. They also indicated that the GETUG 15 had a significantly higher proportion of men receiving “salvage” docetaxel perhaps contributing to the non-significant improvement in OS in those men. They also pointed out that the CHAARTED trial had fewer men who discontinued treatment early due to toxicity compared to the GETUG 15 trial (12.5% vs 20%) and it may therefore be a better reflection of the OS in patients who can tolerate this therapeutic approach.
Overall Doctors Small and Yu generally agreed that men with hormone-sensitive mPCa and high volume disease should be treated with docetaxel in addition to ADT and that the jury is still out regarding men with low-volume disease. We must wait for the results from additional trials (including STAMPEDE) to help answer the question about the value of docetaxel in newly diagnosed, ADT naïve men.
Conclusion- The results of the CHAARTED trial remains a game changer in the treatment of men with significant disease who are ADT naïve.
Joel T. Nowak, M.A., M.S.W.
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