Vogelzang Sees Early Chemo Strategy as Landmark Change in Prostate Cancer Therapy

Nicholas J. Vogelzang, MD

Ten years ago, Nicholas J. Vogelzang, MD, helped design a study of docetaxel added to first-line androgen deprivation therapy (ADT) in men with newly diagnosed metastatic, hormone-sensitive prostate cancer.

He expected the combination to demonstrate a benefit over the standard treatment of hormone therapy alone, but he wasn’t prepared for the practice-changing results the trial generated: a nearly 14-month overall survival (OS) advantage in the chemotherapy-plus-ADT arm. The survival benefit was greatest for men with extensive disease spread.

The findings from the federally funded, randomized phase III study, CHAARTED (E3805),¹ were reported during the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting in June.

“I feel that we have changed the paradigm,” said Vogelzang, who treats patients at the Comprehensive Cancer Centers of Nevada and helps lead clinical research for the US Oncology Network, in an interview with OncLive. “This is the first big change in the treatment of hormone-sensitive, metastatic prostate cancer since the 1940s. It’s a pretty impressive change.”

Until now, in prostate cancer, docetaxel generally has been used only in disease that progressed after treatment with ADT. Rarely, and off-label, doctors have used the chemotherapy as first-line treatment, in combination with ADT, for this patient population, Vogelzang said.

Since both drugs are available and approved for use in prostate cancer, Vogelzang expects the new combination strategy to be immediately incorporated into practice; he, for one, is already using it to treat newly diagnosed patients with high-risk disease. He said guideline changes are already in the works, and added that the strategy “should be very readily adopted by community doctors.”

Key Findings Released at ASCO

Making the regimen even more accessible is the fact that its cost is expected to be relatively low, since both agents are available in generic form, Vogelzang said. “The biggest cost is probably the anti-nausea drugs, and this is not a particularly nausea-inducing regimen, so the cost is pretty modest,” he said.In the 8-year, National Cancer Institute (NCI)-led study, 790 men with newly diagnosed metastatic prostate cancer—two-thirds of them with high-extent disease—were randomly assigned 1:1 to receive either ADT alone or ADT with docetaxel, which was dosed at 75 mg/m² every 3 weeks for 6 cycles within 4 months of starting ADT. After the combination cohort completed 6 courses of docetaxel, all patients continued on ADT alone. The patients were stratified so that the study arms would be balanced, said Christopher Sweeney, MBBS, a medical oncologist at the Lank Center of Genitourinary Oncology at the Dana-Farber Cancer Institute in Boston who presented the study’s findings at a June 1 press briefing during the ASCO meeting.

At a median follow-up of 29 months, median OS was 44 months in the ADT group and 57.6 months in the ADT-plus-docetaxel group, or a 39% higher likelihood of survival in the combination arm at any study time point (hazard ratio 0.61, P = .0003), Sweeney reported. The relative improvement in median OS was largest (32.2 months ADT-only versus 49.2 months combination) among the 520 patients with high-extent disease, who had either 4 or more bone metastases or liver or lung metastases, he said. Patients with low-extent disease respond better to ADT, and thus the median OS for this subset has not yet been reached.

Docetaxel also delayed disease progression. At 1 year, the proportion of patients with prostate-specific antigen (PSA) levels ˃0.2 ng/mL (considered a sign of a better remission) was 11.7% in the ADT group versus 22.7% in the ADT-plus-docetaxel group, Sweeney said. The median time to clinical progression (new symptoms or metastases detected on a scan) was 19.8 months in the ADT group versus 32.7 months in the ADT-plus-docetaxel group, he said, and the measuring time to the development of CRPC—whether determined due to a rise in PSA, new symptoms, or scan—was 14.7 months in the ADT group and 20.7 months in the ADT-plus-docetaxel group.

“In prostate cancer, I am not aware of a historical study that ever offered up this magnitude of improvement in survival,” ASCO President Clifford A. Hudis, MD, chief of the Breast Cancer Medical Service at Memorial Sloan Kettering Cancer Center in New York City, said during the briefing. “Across all solid tumors, this is an almost unprecedented improvement in median survival, and I think it can be transformative for people.”

Adverse events in the trial included febrile neutropenia (4% grade 3, 2% grade 4) and grade 3 neuropathy (1% sensory, 1% motor), the authors reported. One of 397 patients who received early docetaxel died due to treatment, while no deaths due to treatment occurred in the ADT-only arm, Sweeney said.

While Vogelzang called the combination “remarkably safe,” he cautioned that, “You’ve got to be careful, because it’s hard to give this to elderly patients; particularly those over 75 have to be treated cautiously. But it should be at least discussed with all patients with newly diagnosed metastatic prostate cancer.”

Rationale for Designing the Study

In a follow-up to the trial, survival benefits for patients with low-extent disease will continue to be assessed. Another subset analysis will look at whether previously treated patients in the trial had worse outcomes than treatment-naïve patients, Vogelzang said. Quality-of-life data from the study will also be analyzed and reported at a later time.The impetus to study the combination began more than a decade ago, as members of Cancer and Leukemia Group B conducted separate trials comparing mitoxantrone and docetaxel against placebo, and “were impressed with the 9- to 12-month survival benefit over no chemotherapy” that they observed with docetaxel, Vogelzang recalled. In a head-to-head comparison, docetaxel demonstrated a survival improvement of 2.5 months over mitoxantrone, he added.

Based on that information, the cooperative group asked the National Cancer Institute (NCI) to conduct two trials—one of adjuvant docetaxel, an idea the NCI rejected, and one of docetaxel added to ADT.

Lingering Questions

“I didn’t think [this study] was as likely to succeed,” Vogelzang recalled, adding that the trial accrued slowly due to patient and investigator ambivalence, and was thus opened up to a group of patients who had lower-risk prostate cancer. “The trial really was a testimony to a lot of persistence on the part of a lot of people and commitment to the drug and to the disease, which had not really been studied very well in the past except [when it came to] hormone therapy.”In contrast to the dramatic results of the CHAARTED study, a smaller French study² among 192 patients with a slightly better prognosis showed little difference in median OS for those who received the combination therapy compared with ADT alone, although there was a 2-year progression-free survival advantage for those patients who also received docetaxel.

The early chemotherapy strategy also is being evaluated as part of the 7-arm STAMPEDE trial,³ a British study seeking to enroll 5000 men that is expected to report results soon, noted Vogelzang.

Vogelzang, however, does not expect any findings to eclipse those generated by CHAARTED. “I don’t see any trial likely to be done that would threaten this data,” he said.

An important lesson from the trial, Vogelzang noted, is that “the idea that we can’t make progress with old drugs is not true; we don’t always know how to give these drugs.”

Questions remain, as well, about how to combine and sequence some of the many newer drugs for patients with prostate cancer, Vogelzang said. One at the top of his mind is whether radium-223 (Xofigo) could be added to a regimen of leuprolide and docetaxel, allowing a variety of different mechanisms to fight drug resistance simultaneously.

“All these are going to require time to work out their drug—drug interactions and their safety,” he said. “We know that hormones play well with others, but if you combine radium-223 with docetaxel, you might have to cut back on the docetaxel. So our combinations might not be A plus B plus C, but maybe AB followed by C to avoid interactions.”

Completing a series of such trials will take more than 10 years, he said.

“The ability to design and conduct these kinds of trials is going to be dependent upon a generation of oncologists,” Vogelzang said.

References

1. Sweeney C, Chen Y-H, Carducci MA, et al. Impact on OS with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer: an ECOG-led phase III randomized trial. Presented at: the 50th Annual Meeting of the American Society of Clinical Oncology; May 30-June 2, 2014; Chicago, Illinois. Abstract LBA2.
2. Gravis G, Fizazi K, Joly F, et al. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial [published online January 8, 2013]. Lancet Oncol. 2013;14(2):149-158.
3. NIH Clinical Trials Registry. www.ClinicalTrials.gov website. Clinical trials identifier: NCT00268476. Updated February 25, 2013. Accessed June 10, 2014.