Kate Johnson

June 01, 2014

CHICAGO — For patients with metastatic hormone-sensitive prostate cancer, upfront chemotherapy with docetaxel, given at the same time as hormone therapy instead of later, prolongs survival. This finding, from the ECOG E3805 CHAARTED trial, is being described as "practice-changing" and "transformative".

Dr. Christopher Sweeney

"This is one of the biggest improvements in survival we have seen in a trial involving patients with an adult, metastatic solid tumor," said lead investigator Christopher Sweeney, MD, from the Dana-Farber Cancer Institute in Boston. "The benefit is substantial and warrants this being a new standard treatment for men who have high-extent disease and are fit for chemotherapy."

The results were highlighted during a press briefing here at the American Society of Clinical Oncology® (ASCO).

"In prostate cancer, I am not aware of a historic study that ever offered up this magnitude of improvement in survival, said ASCO president Clifford Hudis, MD, during the press briefing. "Quite frankly," he said, "across all of solid tumors, this is an almost unprecedented improvement in median survival."

"These results demonstrate how we can use old tools in new and more powerful ways to improve and extend patients' lives," Dr. Hudis explained.

These are "big time data that will have a strong impact on a small subset of men with metastatic prostate," said Andrew Armstrong, MD, associate professor of medicine and surgery at the Duke Cancer Institute in Durham, North Carolina.

"I anticipate that it will change practice," he told Medscape Medical News.

 
I anticipate that it will change practice.
 

Initial E3805 results were released in December 2013 after the independent Data and Safety Monitoring Committee overseeing the trial recommended that the National Cancer Institute do so.

"We saw a benefit and did a limited press release in accordance with public health need," Dr. Sweeney told Medscape Medical News.

The updated results, with a median follow-up of 29 months, have been eagerly awaited by prostate cancer specialists, said Dr. Armstrong, who sits on the National Comprehensive Cancer Network's (NCCN) guidelines panel for prostate cancer.

"The vast majority of people haven't yet changed their practice based on that press release, but they may change it after seeing these data. As an NCCN panel member, I can say we obviously have to examine the data before we discuss changing our algorithm for treatment," Dr. Armstrong explained.

Improved Overall Survival

The study evaluated 790 men with metastatic hormone-sensitive prostate cancer who received androgen-deprivation therapy (ADT). Of this cohort, 397 were randomized within 4 months of starting ADT to receive docetaxel 75 mg/m² every 3 weeks for 6 cycles.

In accordance with the current standard of care, the 129 patients who progressed on ADT alone were eventually given docetaxel.

As of January, there were fewer deaths with ADT plus docetaxel than with ADT alone (104 vs 137), and median overall survival was longer with the combination (57.6 vs 44.0 months; hazard ratio [HR], 0.47; = .0003).

The combination, compared with ADT alone, was particularly effective in the 520 men with high-volume disease, where the increase in survival was 17 months (median overall survival, 49.2 vs to 32.2 months; HR, 0.60; = .0006).

The number of patients who had a significant and major suppression of their prostate-specific antigen (PSA) level was doubled with the combination, "both at the 6-month mark and the 12-month mark," Dr. Sweeney reported.

And median time to progression — an elevation in PSA level, new symptoms, or worsening scans — was significantly longer with the combination than with ADT alone (20.7 vs 14.7 months; P < .001), as was median time to the harder end point of clinical progression (32.7 vs 19.8 months; P < .001).

Toxicities associated with combination included fever with suppressed white cell count in 6%, and "there was a significant impact on nerve function," he said. Also, "1% of 397 patients who received docetaxel died due to treatment."

"The results of this study represent the first major breakthrough in the treatment of newly diagnosed metastatic prostate cancer in several decades," said Nancy Dawson, MD, professor of medicine at the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC. "These results should change the standard of care for men with hormone-sensitive widespread prostate cancer."

Describing the results as "outstanding," study discussant Michael Morris, MD, from the Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College in New York City, said that "if you look at every drug that prolongs survival in castration-resistant disease, none even comes close" to providing as much benefit as docetaxel given in this way.

"Our best therapies in metastatic castration-resistant disease are less than a third of that, he noted. "This has direct bearing on the ongoing dialogue about cost vs value for cancer care that's going on right now in the country. Clearly, the cost of an off-patent drug such as docetaxel is going to be lower than on-patent drugs that characterize our newer therapies."

Dr. Morris explained that clinicians can have an impact on value by deciding how and when docetaxel is used in the setting of metastatic prostate cancer. "You could apply docetaxel in castration-resistant disease [after hormone therapy has stopped working] and gain 81.2 days in overall survival for $15,000, or apply it to appropriately selected patients with castration-sensitive disease [while hormone therapy is still effective] and gain 476 days in overall survival for $9000."

But he stressed the importance of patient selection, noting that "there are insufficient data at this time after 29 months of median follow-up to recommend that low-volume patients with castration-sensitive disease undergo chemotherapy."

"We need to be able to identify the appropriate high-volume patients who are chemotherapy candidates and we have to be able to identify those who should be spared chemotherapy, for whom there is no proven survival benefit, at least at this juncture," Dr. Morris said. "We do need to optimize the distinction."

"This is a great study and a very important advance for patients," Gwenaelle Gravis, MD, from the Institut Paoli-Calmettes at the Centre de Recherche en Cancérologie de Marseille in France, told Medscape Medical News.

Dr. Gravis was involved in the GETUG-AFU 15 study, which is the "major challenge" to the new E3805 results, Dr. Morris explained. It examined the same treatments in the same patient population and found no benefit to early docetaxel (Lancet Oncol. 2013;14:149-158).

However, GETUG-AFU 15 was much smaller than E3805, and "the number of patients in the ADT-only arm who received subsequent docetaxel for disease progression was 31% in E3805 and 62% in our study," Dr. Gravis reported.

GETUG-AFU 15 also had much fewer high-volume patients, said Dr. Morris. "For these reasons, I think that GETUG-AFU 15 does not refute the fact that high-volume patients benefit from chemotherapy. If anything, it confirms that low-risk or low-volume patients should not get chemotherapy until there is better evidence," said Dr. Morris.

The study was funded by the National Institutes of Health. Dr. Sweeney reports financial relationships with Sanofi. Dr. Armstrong, Dr. Gravis, and Dr. Dawson have disclosed no relevant financial relationships. Dr. Morris reports financial relationships with Agensys, Algeta, Astellas Pharma, Bayer, Biogen Idec, Fujifilm, Janssen Pharmaceuticals, Medivation, Millennium, Procter & Gamble, Progenics, Sanofi, and Teva.

2014 Annual Meeting of the American Society of Clinical Oncology (ASCO): Abstract LBA2. Presented June 1, 2014.

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