Should Docetaxel Be Standard of Care for Patients With Metastatic Hormone-Sensitive Prostate Cancer? Pro and Contra

K. Fizazi; C. Jenkins; I. F. Tannock

Disclosures

Ann Oncol. 2015;26(8):1660-1667. 

In This Article

Abstract and Introduction

Abstract

Following the results of the TAX-327 study, questions have been raised as to whether administering chemotherapy to men with prostate cancer before symptomatic disease progression when receiving standard hormonal treatment can improve the duration and quality of patient survival. The GETUG-AFU-15 and CHAARTED studies both assessed the efficacy and tolerability of androgen deprivation therapy (ADT) with or without docetaxel in men with metastatic hormone-naive prostate cancer. Both studies included a mix of patients with de novo metastatic disease (~75%) and patients who developed metastases following treatment of localized disease. A short course of ADT was allowed in both trials prior to accrual. Key differences between the two studies include the number of patients with high-volume metastases (GETUG-AFU-15: 52%; CHAARTED: 65%) and number of docetaxel cycles (GETUG-AFU-15: up to nine cycles; CHAARTED six cycles). Both studies reported an improvement in progression-free survival with docetaxel plus ADT versus ADT alone. The GETUG-AFU-15 did not find a significant difference in the primary end point of overall survival (OS) {hazard ratio (HR) 0.9 [95% confidence interval (CI) 0.7–1.2]; P = 0.44} for ADT plus docetaxel versus ADT alone. The CHAARTED study met the primary end point of OS [HR 0.61 (95% CI 0.47–0.80); P = 0.0003], and in a subset analysis reported the greatest improvement in OS for patients with high-volume disease [HR 0.60 (95% CI 0.45–0.81); P = 0.0006]. The following article debates the results from the GETUG-AFU-15 and CHAARTED studies and asks whether medical practice should be changed for patients with metastatic hormone-naive prostate cancer based on the results of one positive study.

Introduction

In the Western world, the majority of men, who are diagnosed with localized prostate cancer, have only localized disease at presentation, but ~20% of men with clinically detected disease have de novo metastases at diagnosis.[1] In countries, such as India and China, with less access to care the incidence of de novo metastatic disease increases dramatically.[2,3] A registry study carried out between 1998 and 2009 reported limited improvement in overall survival (OS) and disease-specific survival among men with de novo metastatic hormone-sensitive prostate cancer.[1] Although de novo metastatic prostate cancer is much less common than localized disease at diagnosis, it remains a cause of prostate cancer-related death. In a retrospective pooled analysis of data from two French hospitals following 190 men with prostate cancer for a median 6.8 years, 116 men died as a result of disease progression. Of these 116 men who died from prostate cancer, 44% had localized disease and 56% had de novo metastatic disease at diagnosis.[4]

Since growth of prostate cancer cells is driven by androgens, androgen deprivation therapy (ADT) is the standard treatment of hormone-naive disease. Despite response to ADT in ~90% of patients, the majority of men progress to castration-resistant prostate cancer (CRPC) within 1–3 years.[5,6] Hormone-sensitive cells may become castration-resistant through adaptation from androgen-dependent to androgen-independent mechanisms as a consequence of genetic/epigenetic alterations. It is also likely that, at disease onset, a small number of cells are hormone resistant and consequently thrive despite a low androgen environment, such as that created by treatment with ADT. Both adaptation of initially hormone-sensitive cells and clonal proliferation of hormone-resistant cells can drive disease progression and resistance to hormone therapy[7] (Figure 1).

Figure 1.

Representation of two models for development of CRPC. In the upper figure all cells are assumed to be initially androgen-sensitive but some of them adapt to become androgen-independent during ADT. In the lower figure androgen-independent cells are assumed to exist in the untreated tumour and ADT leads to selection of androgen-independent clones.

In 2004, following results from the TAX 327 study, docetaxel was approved as first-line chemotherapy for treatment of patients with metastatic CRPC and was the first drug to demonstrate improved survival in this setting. OS with mitoxantrone plus prednisone, docetaxel plus prednisone every 3 weeks and docetaxel every week was 16.3, 19.2 and 17.8 months, respectively [hazard ratio (HR) for death in the 3-weekly docetaxel group versus mitoxantrone group: 0.79; 95% confidence interval (CI) 0.67–0.93; P = 0.004].[8,9] The SWOG-9916 study also demonstrated improved OS for docetaxel plus estramustine compared with mitoxantrone plus prednisone in such patients.[10] Following approval of docetaxel for first-line treatment of metastatic CRPC (mCRPC), a relevant question is whether administering chemotherapy to patients who are sensitive to hormone therapy can improve the efficacy and tolerability of docetaxel and improve patient outcomes. This review provides an overview of the two clinical trials evaluating ADT plus docetaxel administered to men with metastatic hormone-sensitive prostate cancer. The data are debated to provide provocative arguments as to whether or not the standard of care for these patients should be changed based on the available results.

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