PerspectiveIn the Journals

Early docetaxel-based chemotherapy may improve survival for high-risk localized prostate cancer

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July 21, 2015

The addition of early docetaxel-based chemotherapy to androgen deprivation therapy improved RFS in patients with high-risk localized prostate cancer, according to phase 3 study results.

Although a standard treatment for breast, colorectal and lung cancers, early risk-stratified chemotherapy is not regularly used in the treatment of high-risk localized prostate cancer, according to study background.

Because the chemotherapeutic combination of docetaxel with estramustine (Emcyt, Pfizer) had previously shown an improvement in survival for patients with castration-resistant prostate cancer, Karim Fizazi, MD, PhD, head of the department of cancer medicine at the Institut Gustave Roussy in Villejuif, France and professor of oncology at the University of Paris, and colleagues sought to assess the effects of the chemotherapy combination on relapse in patients with high-risk localized prostate cancer.

Karim Fizazi, MD

Karim Fizazi

“As far as we know, this trial is the most advanced randomized trial testing the role of early docetaxel chemotherapy in localized prostate cancer at high-risk for relapse,” Fizazi told HemOnc Today. “With more than 8 years of median follow-up, the current results show for the first time that docetaxel significantly reduces the risk for relapse or death by approximately 30%. The immediate and long-term toxicity seems clearly acceptable, with no toxic death and no excess second cancers.”

RFS served as the study’s primary endpoint. Secondary endpoints included clinical RFS, metastases-free survival, OS, PSA response, toxicity and quality of life.

Researchers randomly assigned 207 patients to the ADT plus docetaxel and estramustine arm and 206 patients to the ADT-only arm. Median follow-up was 8.8 years (range, 8.1-9.7).

In the docetaxel-based chemotherapy arm, 43% of the patients experienced an event — defined as biochemical failure, an onset of metastases on imaging, proven local relapse, use of salvage treatment or death — compared with 54% of patients on the ADT-only arm.

A greater proportion of patients in the docetaxel group achieved 8-year RFS (62%; 95% CI, 55-69) than patients in the ADT-only group (50%; 95% CI, 44-57; adjusted HR = 0.71; 95% CI, 0.54-0.94).

Of the 151 patients in the docetaxel arm who were treated with radiotherapy and had available data, 21% experienced a grade 2 or higher long-term toxicity, which was not statistically different from the 18% of 143 eligible patients who experienced a grade 2 or worse long-term toxicity in the ADT-only arm.

Researchers reported no excess of second cancers in the docetaxel arm (13% vs. 11%), and no treatment-related deaths occurred.

“We keep following these patients and our plan is to assess the important endpoints of metastases-free survival and OS several years from now,” Fizazi said. “We believe that this will help establish the role of early docetaxel-based chemotherapy in this disease.”

Andrew J. Armstrong, MD, ScM, FACP

Andrew J. Armstrong

In an accompanying editorial, Andrew J. Armstrong, MD, an associate professor of medicine and surgery at Duke University School of Medicine, wrote it is important to note estramustine has fallen out of favor as a chemotherapeutic option since this trial was initiated in 2002. Further, he acknowledged that the researchers were not able to define clinically meaningful and approvable surrogate endpoints for localized prostate cancer.

However, these results continue to build the case that chemotherapy can be an effective part of treatment of prostate cancer, even in its early stages, Armstrong added.

“[This study] adds to the growing evidence challenging the dogma that chemotherapy is ineffective in prostate cancer and suggests that early docetaxel can safely delay progression,” Armstrong wrote. “Whether this delay can increase life expectancy will need to be addressed in larger well-powered studies.” – by Anthony SanFilippo

For more information:

Karim Fizazi, MD, PhD, can be reached at the Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France; email: karim.fizazi@gustaveroussy.fr.

Disclosure: This study was funded in part by Sanofi-Aventis and AstraZeneca. Fizazi reports honoraria from and an advisory role with Sanofi-Aventis. The other researchers report no relevant financial disclosures.

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PERSPECTIVE
Christopher Sweeney

Christopher Sweeney

The goal of any basic and clinical cancer research is to develop new strategies that will help decrease deaths from cancer. Successful strategies include integrating and/or combing active single-agent therapies, be it local therapy plus systemic therapy for micro-metastatic disease (eg, colon cancer, breast cancer, prostate cancer, head and neck cancer) or combination chemotherapy (eg, CHOP plus rituximab [Rituxan; Genentech, Biogen Idec] for non-Hodgkin’s lymphoma; BEP chemotherapy for germ cell tumors). It is therefore logical to assess drugs active in castration-resistant prostate cancer (CRPC) and add them to adjuvant androgen deprivation therapy plus radiation for high-risk localized prostate cancer. It is also plausible that agents active in CRPC are at least, if not more, active in the lower tumor burden and more sensitive setting of micrometastatic disease (ie, adjuvant to radiation and/or prostatectomy).
Therefore, it is plausible that the combination of local therapy (predominantly radiation) ADT plus docetaxel-based chemotherapy as done in GETUG 12 will decrease relapses and decrease death from prostate cancer more than seen with ADT plus radiation alone. When patients also have access to the many new active therapies for CRPC, the data from the CHAARTED and STAMPEDE trials — which showed a significant improvement in OS when docetaxel was added to therapy for metastatic hormone-sensitive prostate cancer — adds encouragement that this strategy in the micrometastatic setting also will be effective. The benefits of improved OS and decreased relapses in the high-risk localized cohort when men are treated with radiation plus ADT plus docetaxel vs. ADT plus radiation alone seen in the RTOG 0521 trial, adds further hope that this strategy will be successful.
The operative word here is hope. Namely, the data to date are not definitive and have not been reproduced showing that adding docetaxel to ADT plus radiation will improve OS. This is because the follow-up from these studies is too short to reliably assess OS and the early clinical endpoints have not been validated as surrogates for OS. To address this, the Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) Working Group has collated the individual patient data on more than 22,000 patients treated with localized therapy on clinical trials and will attempt to define a reliable and robust intermediate clinical endpoint for prostate cancer-specific survival and OS. The data from the patients with ADT plus radiation with or without docetaxel will also be combined in a meta-analysis to see if an OS benefit is seen with the aggregate data and/or whether the potentially robust surrogate endpoint is met.
So, in short, that the GETUG 12 data set shows a decreased relapse rate is encouraging but is not enough to change therapy. However, it is possible the international collaborative efforts and aggregation of data under the auspices of the ICECaP Working Group will hopefully provide clarity in 2016.
References:

Sandler HM, et al. Abstract LBA5002. Presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.

Sweeney C, et al. Abstract LBA2. Presented at: ASCO Annual Meeting; May 30-June 3, 2014; Chicago.

James ND, et al. Abstract 5001. Presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.


Christopher Sweeney, MBBS
Dana-Farber Cancer Institute
Harvard Medical School

Disclosure: Disclosure: Sweeney reports consultant roles with and honoraria from Astellas, AstraZeneca, Bayer, BIND therapeutics, Genentech, Janssen and Sanofi.