Zosia Chustecka

May 13, 2015

The largest ever randomized trial in prostate cancer has shown that adding chemotherapy upfront to hormone therapy significantly improves overall survival. This is the second trial to show a survival benefit from using chemotherapy upfront, and has experts talking again about a paradigm shift.

"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," commented American Society of Clinical Oncology (ASCO) President Peter Yu, MD, who is director of cancer research at the Palo Alto Medical Foundation in Mountain View and Sunnyvale, California.

But now there are data suggesting that this may be the wrong strategy, he continued, and that using chemotherapy upfront may be better than using it as a last resort.

However, another expert is dismayed at the "hype" that has surrounded the studies of using docetaxel upfront, and has cautioned that the data need to be reported in a full-length manuscript and analyzed in detail before practice changes are made.

New Results From British Trial

The new results come from an analysis of nearly 3000 patients from the British STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) trial.

Men with newly diagnosed advanced prostate cancer who were starting on androgen-deprivation therapy (ADT) lived on average for 10 months longer when docetaxel was given together with the hormone therapy.

Patients with metastatic disease benefited most profoundly, with a median survival benefit of 21 months.

Study results were presented during a press briefing held in advance of the ASCO 2015 Annual Meeting.

"We hope our findings will encourage doctors to offer docetaxel to men newly diagnosed with metastatic prostate cancer, if they are healthy enough for chemotherapy. Men with locally advanced nonmetastatic prostate cancer may also consider docetaxel as part of upfront therapy, as it clearly delays relapse," lead author 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, commented in a statement.

This is the second study to show that adding chemotherapy up front can improve survival. At last year's ASCO meeting, the results of the American CHAARTED study were hailed as practice-changing. This study, conducted in 790 patients, showed that adding docetaxel to ADT improved median overall survival by 13.6 months, with the greatest benefit seen in men with high-volume metastatic disease, in whom median overall survival was 17.0 months longer.

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

This latest trial from the United Kingdom is larger than both of these previous studies, and had a broader patient population, involving about 1800 men with metastatic disease and 1200 with high-risk nonmetastatic prostate cancer.

"This is the biggest study of its kind and it strongly suggests that adding chemotherapy to standard hormone therapy can extend the lives of men with advanced prostate cancer," Dr Yu commented in a statement.

Dr Yu also praised the innovative design of the study.

The STAMPEDE study is an ongoing study with a multistage, multigroup design, which can be modified to drop therapies proven to be ineffective, add new therapies to be evaluated, and also can adapt to changes in the standard of care. For instance, while the trial was in progress, radiation was added to the standard of care of ADT for certain patients.

The multigroup design of the trial also allowed the researchers to test whether adding the bone-targeting drug zoledronic acid (Zometa, Novartis) provided any extra benefit. The results show that it does not.

Metastatic and High-Risk Disease

The results presented by Dr James and colleagues at the meeting come from an analysis of 2962 men with newly diagnosed advanced prostate cancer. About 60% had metastatic disease, the rest had high-risk locally advanced nonmetastatic disease (either node-positive, or with two of three of the following risk factors: stage T3/T4, PSA ≥ 40 ng/mL, or Gleason sum score of 8–10).

All of these men received standard of care, which was at least 3 years of ADT, with radiation for patients who were suitable. In addition, some men also received docetaxel for six cycles, zoledronic acid for 2 years, or both docetaxel and zoledronic acid.

After a median follow-up of 42 months, 948 men had died.

The addition of docetaxel significantly improved median overall survival to 77 months, compared with 67 months for ADT alone.

For the subgroup of patients with metastatic disease, 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, Dr James said at the press briefing, and he suggested that clinical guidelines will be changed soon to incorporate such a recommendation.

However, in the other subgroup of patients with advanced but not metastatic disease, the difference in survival was not statistically significant, but these survival data are still immature, Dr James noted. However, docetaxel prolonged the event-free survival by "a substantial amount," and so it should also be considered in this group, he said.

There was an increase in toxicity with the addition of docetaxel. Grade 3/4 toxicity was reported by 30% of patients in the standard of care group, by 50% of patients who also took docetaxel, by 32% of patients who also took zoledronic acid, and by 50% of patients who also took both docetaxel and zoledronic acid.

However, the researchers say the adverse effects were "manageable," and add that very few patients discontinued because of them.

"View With Extreme Caution"

Approached for comment, 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, 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."

Dr Garnick pointed out that, to his knowledge, none of the three key studies have been published as full-length peer-reviewed manuscripts. "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.

Another concern is that based on the abstract data, there is no ability to see who did or did not have access to recently emerging second- and third-line therapies, he said. "The main question I raise is whether the sequencing of the novel second- and third-line therapies, such as abiraterone or enzalutamide, after initial development of metastatic castration-resistant prostate cancer then followed by chemo is better, worse, or the same as initiation of chemo–hormonal therapy earlier."

"Toxicity in this population needs to be fully vetted, especially in the likely population who will receive chemo," Dr Garnick continued. "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."

Overall, Dr Garnick said that he is "dismayed by the hype that has surrounded the endorsement of the much earlier use of docetaxel without the requisite data that can be analyzed to make decisions. That notwithstanding, some data seem to be tending to the potential use of chemotherapy. Only after a more meticulous evaluation of published data from GETUG-AFU 15, STAMPEDE, and CHAARTED will those charged with the care and treatment of these patients be able to make informed choices."

The study was funded by Cancer Research UK and the Medical Research Council, and also received support from Novartis, sanofi-aventis, Pfizer, Janssen, and Astellas. Dr James reports consulting for and/or being on the speaker's bureau for Sanofi, Bayer, Merck, Astellas, Janssen, Pierre Fabre, and Ferring; and receiving honoraria (institutional) from Janssen, Astellas, Pfizer and Sanofi. Some of his coauthors report consulting and other agreements with several pharmaceutical companies. Dr Yu reports stock and other ownership interests with ContraFect, Citrix Systems, EMC Corp., Google, IBM, Oracle, FireEye, and Apple; and receiving research funding from Berg Pharmaceuticals.

American Society of Clinical Oncology (ASCO) 2015 Annual Meeting: Abstract 5001. To be presented May 31, 2015.


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