Paradigm Shift in Prostate Cancer: Early Chemo With ADT

Zosia Chustecka

August 06, 2015

The first trial to show that using chemotherapy early on in the treatment of prostate cancer can improve survival was published online August 5 in the New England Journal of Medicine.

Traditionally, the initial treatment for men with newly diagnosed prostate cancer is hormonal therapy, and chemotherapy is used only when the disease is no longer responsive (castration-resistant).

But the ECOG E3805 CHAARTED trial showed that adding docetaxel chemotherapy to androgen-deprivation therapy (ADT) in men with newly diagnosed metastatic disease dramatically improved survival, by more than a year compared with the use of ADT alone.

Since the presentation of these results last year, at the 2014 annual meeting of the American Society of Clinical Oncology (ASCO), another large trial has also shown a survival benefit from adding chemotherapy upfront, leading both sets of the authors and several outside experts to talk of a paradigm shift in the management of newly diagnosed metastatic prostate cancer.

However, at least one expert has urged caution, pointing out that many men do well on hormonal therapy alone, and that chemotherapy (for 18 weeks) adds toxicity in an elderly patient population.

Reacting now to the publication of the CHAARTED study on behalf of the American Urological Association (AUA), Michael Cookson, MD, professor and chair of the Department of Urology at the University of Oklahoma Health Sciences Center in Oklahoma City said: "This important trial is a game-changer."

He said the data are practice-changing.

"Previously, chemotherapy was reserved for men who had failed hormone therapy, who were castration-resistant," he explained, and in those cases, the use of chemotherapy would improve survival by about 3 months, on average. But using chemotherapy upfront together with hormone therapy when the patient is newly diagnosed with metastatic prostate cancer improved survival by a median of a year, and some patients had survival improvements of 18 months or more, he pointed out.

"So we do believe that this is a paradigm shift in the management of men who present with newly diagnosed metastatic disease," Dr Cookson told Medscape Medical News.

"For men like the ones in this trial with bone metastases and clear radiological evidence of disease, they should be initiated on hormonal therapy and have a discussion about the potential added benefits of adding chemotherapy to hormone treatment, and then have a referral to a medical oncologist early in the decision making, rather than waiting until much later," he said.

"Definitely, chemotherapy upfront should be considered for patients with newly diagnosed metastatic disease who are 'chemo-fit'," commented lead author of the CHAARTED study, Christopher Sweeney, MBBS, from Dana-Farber's Lank Center for Genitourinary Oncology in Boston.

"It is now required that physicians talk to these patient about the option of chemotherapy upfront," Dr Sweeney told Medscape Medical News, adding that it would be "incorrect" now to go ahead and just use hormone therapy alone in view of the data from the two large studies showing a survival benefit from the addition of chemotherapy.

This change in management calls for closer collaboration between urologists, who often initially diagnose prostate cancer and prescribe hormonal treatment, and medical oncologists, who administer chemotherapy, commented Dr Cookson. The use of both of these modalities together upfront in the treatment of prostate cancer means that these two groups of clinicians will have to collaborate more closely, Dr Cookson said.

At present, the AUA does not have published guidelines for this group of patients newly diagnosed with hormone-sensitive prostate cancer, and this is an unmet need, he said; the publication of these new results suggest this is an "optimal time" to draw up such guidelines.

The AUA has published guidelines that cover localized disease and castration-resistant disease; the downstream effect of the change in management of newly diagnosed metastatic disease will have a big effect on the treatment of castration-resistant disease, Dr Cookson commented, so that guideline (on which he is first author) will need revision.

Dr Sweeney noted that the National Comprehensive Cancer Network has already incorporated the new findings into its guidelines, and lists chemotherapy upfront as a treatment option with a category 2a recommendation, based on the ASCO presentation of the data. Now that the data have been published and peer reviewed, that recommendation may be upgraded to grade 1, Dr Sweeney said.

Based on anecdotal data, he believes that the data have already changed practice. Although it is difficult to measure use of docetaxel because it is available generically, Dr Sweeney says that clinicians have told him they are now using the chemotherapy upfront, and started to do so after hearing the 2014 ASCO presentation, as "they felt the data were robust and the effect was large."

There haven't been any problems with insurance coverage in the United States for this use of chemotherapy in prostate cancer as far as he is aware, Dr Sweeney commented.

"The longevity gained from an 18-week course of docetaxel, and the cost of a generic drug, would make it a very viable option for those who are chemo-fit," Dr Sweeney said.

Study Details

The ECOG E3805 CHAARTED trial was conducted in 790 patients (median age, 63 years) with newly diagnosed metastatic hormone-sensitive prostate cancer. Traditionally, such patients would be initially treated with ADT, but in this trial half were randomized to also received docetaxel (at a dose of 75 mg/m² of body-surface area every 3 weeks for six cycles).

After a median follow-up of 28.9 months, the median overall survival was 13.6 months longer with the combination, at 57.6 months vs 44.0 months on ADT alone (hazard ratio for death in the combination group, 0.61; P < .001).

The median time to disease progression (biochemical, symptomatic, or radiographic progression) was 20.2 months in the combination group, compared with 11.7 months in the ADT-alone group (hazard ratio, 0.61; P < .001).

The downside was adverse events typically seen with docetaxel, and in the combination group, the rate of grade 3 or 4 febrile neutropenia was 6.2%, the rate of grade 3 or 4 infection with neutropenia was 2.3%, and the rate of grade 3 sensory neuropathy and of grade 3 motor neuropathy was 0.5%.

Dr Sweeney said that the data in the publication have not changed substantially from when they were initially presented last year, when the trial was hailed as "transformative," as reported at the time by Medscape Medical News.

"The results of this study represent the first major breakthrough in the treatment of newly diagnosed metastatic prostate cancer in several decades," Nancy Dawson, MD, professor of medicine at the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, said at the time.

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. He also pointed out that docetaxel is available generically, and so is much cheaper than the new drugs.

Second Study, Paradigm Shift

Since then, another even larger study has also shown a survival advantage from using chemotherapy upfront. Earlier this year, at the 2015 annual ASCO meeting, results were presented from the British STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) trial. The researchers presented an analysis from 2962 men with newly diagnosed prostate cancer with a median follow-up of 42 months, which showed that men treated with chemotherapy plus ADT live for about 10 months longer, with a median overall survival of 77 months, compared with 67 months for ADT alone.

For the subgroup of patients with metastatic disease (which matches the patients in the CHAARTED trial), the survival benefit was even greater, with median overall survival of 65 vs 43 months on ADT alone.

For this group of men with newly diagnosed metastatic prostate cancer, docetaxel upfront should become routine practice, principal investigator Nicholas David James, MD, PhD, director of the cancer research unit at the University of Warwick and consultant in clinical oncology at the Queen Elizabeth Hospital Birmingham, United Kingdom, said at the time.

Reacting to the presentation, ASCO President Peter Yu, MD, director of cancer research at the Palo Alto Medical Foundation in Mountain View and Sunnyvale, California, said that these data on chemo upfront from a second study suggest it is time for a paradigm shift in the management of prostate cancer.

"The paradigm for years has been to treat prostate cancer with hormone therapy...until there is no response left, and then we try chemotherapy. But this is a self-defeating strategy, because you are using chemotherapy when the disease has gotten to a point where it is much more aggressive," he said. The new data suggest that this may be the wrong strategy, he continued, and that using chemotherapy upfront may be better than using it as a last resort.

Too Early for Practice Change?

However, some experts wondered if it was too early to make practice changes. Approached for comment earlier this year, Marc B. Garnick, MD, Gorman Brothers Professor of Medicine at the Beth Israel Deaconess Medical Center in Boston and editor-in chief of the Harvard Medical School Annual Report on Prostate Diseases, was concerned about hype over the news, and said that the results so far should be "viewed with extreme caution before the combination of chemotherapy and hormonal therapy becomes the new norm, especially with one negative study."

An earlier, smaller study from France — GETUG-AFU 15 — found no benefit to early docetaxel (Lancet Oncol. 2013;14:149-158).

"Toxicity in this population needs to be fully vetted, especially in the likely population who will receive chemo," Dr Garnick commented. "Docetaxel has some significant toxicities and exposure to a patient population who could enjoy a long remission with hormonal therapy (without exposure to chemo and its attendant toxicities) needs to be considered."

Dr Garnick was concerned about basing practice changes on data that had not yet been published as full-length peer-reviewed studies. "To incorporate fairly dramatic changes — i.e., chemotherapy in a likely elderly population, with comorbidities — without the full access to all of the data seems premature," he told Medscape Medical News.

With the publication of the CHAARTED results, one of those cautions no longer applies. "We've crossed that hurdle," Dr Sweeney, lead author on the study, commented in an interview with Medscape Medical News. He acknowledged the importance of having the data published and peer-reviewed, and said the data are now available for clinicians around the world to study and reflect upon how these findings fit in with guidelines.

Turning to the negative trial, Dr Sweeney pointed out that it was conducted several years earlier than the two larger positive studies. Although the GETUG-AFU 15 trial did not show an improvement in survival, it did show a significant improvement in progression-free survival, he noted. However, once these patients progressed, there were very few therapies available to use as salvage at that time. In contrast, by the time the CHAARTED and STAMPEDE studies were in progress, a number of new drugs for use in prostate cancer had become available, including abiraterone (Zytiga), enzalutamide (Xtandi), sipuleucel-T (Provenge), radium-223 dichloride(Xofigo), and cabazitaxel (Jevtana), and could be used as salvage therapies.

The difference in the salvage use of these new therapies in the CHAARTED and STAMPEDE studies probably contributed to the significant survival benefit seen in these two trials, whereas the patients in GETUG-AFU 15 didn't have access to these drugs because they weren't on the market at that time, Dr Sweeney speculated.

There has been some question over whether the volume of the tumor should be taken into account. Both the CHAARTED and STAMPEDE studies were positive for a benefit in the overall patient population, including both high- and low-volume patients, Dr Sweeney pointed out, but in the CHAARTED study, when "we teased out the high-volume patients (a prospective stratification), we saw that the early signal was driven by the high-volume group." This has been interpreted by some researchers as suggesting that the strategy of chemotherapy upfront is suitable only for men with high-volume disease.

"Some men with low-volume tumors do well for years on hormonal treatment alone," Dr Sweeney acknowledged, but he argued that the trial results do not show that men with low-volume tumors do not benefit, just that it takes longer to see if they do benefit. "It's very clear that chemotherapy upfront is of benefit in men with high-volume disease who are chemo-fit, but I also use this strategy in men with low-volume disease who are chemo-fit after going through the risks and benefits with them," he said.

"It comes down to risk stratification," Dr Sweeney said. An 82-year-old man with low-volume metastatic disease and other health issues would probably not get the survival benefit from using chemotherapy upfront, he said. However, for a man with low-volume disease who is 65 years old with another 5 to 8 years' life expectancy and no other health issues, the early chemotherapy may result in a longer remission and a longer cancer control, he added.

Supported in part by a grant from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, and by grants from the Public Health Service. Sanofi provided the docetaxel and a grant to ECOG-ACRIN. Dr Sweeney reports receiving a grant from the National Cancer Institute. Several coauthors report relationships with numerous pharmaceutical companies, as detailed in the publication.

N Engl J Med. Published online August 5, 2015. Abstract

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