Should docetaxel be administered earlier in prostate cancer therapy?

Abstract

Three randomized studies examining docetaxel early in metastatic prostate cancer were recently reported. The CHAARTED and STAMPEDE studies showed a survival benefit for docetaxel when started with androgen suppression therapy in men with newly diagnosed metastatic prostate cancer. The STAMPEDE study also included men with biochemically relapsed prostate cancer. The benefit was a median of 13.6 months in the CHAARTED study and 10 months in STAMPEDE. The survival benefit in CHAARTED was stronger in those with high volume disease. The benefit in STAMPEDE was greater in metastatic, rather than biochemically relapsed, prostate cancer. The third study, GETUG-AFU 15, was a smaller study without a survival benefit. These data have changed how we treat metastatic prostate cancer at our centers, as we now offer all men with metastatic castration sensitive prostate cancer docetaxel chemotherapy upfront.

Keywords:

• chemotherapy
• docetaxel
• metastatic disease
• overall survival
• prostate cancer

Androgen suppression, first advanced by Huggins and Hodges, remained the principal systemic therapy for metastatic prostate cancer for over 60 years, until docetaxel chemotherapy emerged in 2004 [1,2]. Docetaxel was the only treatment capable of extending survival in metastatic castration-resistant prostate cancer (mCRPC) until 2010–2014 when studies of sipuleucel-T [3], cabazitaxel [4], abiraterone [5,6], enzalutamide [7,8] and radium-223 [9] also demonstrated improved survival. Studies of abiraterone and enzalutamide demonstrated that treatment not only extended survival and delayed disease progression, but delayed the need for chemotherapy [6,7]. As docetaxel’s benefits in mCRPC are modest and come at a price of significant toxicity, delaying chemotherapy was thought to be a worthy accomplishment.

The results of three clinical trials, GETUG-AFU 15 [10], CHAARTED [11] and STAMPEDE [12], have revitalized interest in docetaxel – this time for metastatic castration-sensitive prostate cancer. Taken together, the results of these studies demonstrate a larger, more compelling benefit from chemotherapy when it is deployed earlier than previously thought.

GETUG-AFU 15 was the smallest study and used a combination of docetaxel and estramustine (DE, n = 192) for nine cycles versus androgen deprivation therapy (ADT, n = 193) with negative results: median survival for ADT + DE was 58.9 months versus 54.2 months for ADT alone (hazard ratio [HR] 1.01, 95% CI: 0.75–1.36, p = 0.955). CHAARTED and STAMPEDE were larger studies testing six cycles of docetaxel (DOC) and both of these studies demonstrated an overall survival benefit. The median survival in CHAARTED was 57.6 months and 44.0 months for ADT + DOC (n = 397) versus ADT alone (n = 393) (HR 0.61, 95% CI: 0.47–0.80, p = 0.0003). STAMPEDE was designed as a multi-arm study, among them ADT (n = 1184) and ADT + DOC (593). Recently reported results demonstrate the advantage of adding docetaxel to ADT in patients with metastatic disease. The median survival in the STAMPEDE study for the ADT + DOC versus ADT alone arms was 77 months versus 67 months, respectively (HR 0.76, 95% CI: 0.63–0.91, p = 0.003). There were also arms with combinations including celecoxib and zoledronic acid, but neither proved beneficial [13].

While the CHAARTED study demonstrated improved survival overall, the benefit was more robustly demonstrated in the more mature and larger ‘high volume’ disease subset: HR 0.60 (95% CI: 0.45–0.81, p = 0.0006) versus HR 0.63 (95% CI: 0.34–1.17, p = 0.1398), in AST + DOC and AST respectively. High-volume disease was defined as the presence of visceral metastases or at least four bone lesions, one of which needed to be outside of the spine and pelvis. The STAMPEDE study presented results in metastatic patients, but did not subdivide between high and low volume. It found a 22-month improvement in median overall survival in the group treated with AST + DOC HR 0.73 (95% CI: 0.59–0.89, p = 0.002).

So how do we apply these results in practice? First, with both CHAARTED and STAMPEDE demonstrating a benefit of the addition of docetaxel to initial ADT in the treatment of metastatic prostate cancer, this combination is now firmly established as the new standard of care. Patients need to be fit for chemotherapy and have metastases. The STAMPEDE results in PSA-only disease are neither compelling enough nor mature enough to extend this approach to those patients, but there is a signal of benefit. The burden of disease is another question. Should we treat patients who meet the CHAARTED definition of ‘high volume’ of disease or all patients with metastatic prostate cancer? The results of STAMPEDE, which did not stratify by extent of metastases, the overall results of CHAARTED, and the favorable hazard ratio for survival in the low-volume subset of CHAARTED all suggest that chemotherapy should be considered in all patients with metastatic disease. However, lower risk patients may calculate the risks and benefits differently from those with more extensive, higher risk disease. Is there a difference between patients who present with metastatic disease from the beginning and those that get there first having presented with clinically localized cancer? We do not know, but despite the fact that the vast majority of patients in both STAMPEDE and CHAARTED presented with metastatic disease, there does not appear to be a compelling reason to approach their care differently.

Studies of docetaxel in mCRPC included prednisone 10 mg daily. The CHAARTED study did not include steroids, whereas the STAMPEDE study used prednisolone 10 mg daily. We do not know if prednisone adds to either efficacy or safety of docetaxel and its use, based on the available data, should be at the discretion of the treating physician.

In this era of very expensive prostate cancer treatments, it is interesting to note that docetaxel is relatively inexpensive. A 2013 comparison of the direct drug costs of generic docetaxel (10 cycles), abiraterone (6 months), cabazitaxel and sipuleucel-T found that the prices were US$6851, 30,000, 34,350 and 93,000, respectively [14]. Drug costs represent only a portion of the costs of care.

The patients treated with chemotherapy in all three studies had toxicities consistent with chemotherapy. In the GETUG-AFU 15 study, there were four (2%) chemotherapy-related deaths and several grade 3–5 toxicities: neutropenia 61 (32%), febrile neutropenia 15 (8%) and fatigue 13 (7%). In the CHAARTED study, there was one (<1%) death, and the grade 3–5 toxicities were fewer than was seen in GETUG-AFU 15: neutropenia 12 (3%), febrile neutropenia 6 (2%) and fatigue 4 (1%). In the STAMPEDE study, there were 10 (<1%) deaths and grade 3–5 toxicities for neutropenia and febrile neutropenia were both 12%.

The driving hypothesis of these trials is that castration-resistant cells are present at diagnosis and that targeting both castration-sensitive and castration-resistant clones at diagnosis is beneficial. At the time these studies were designed, there were only two treatments with a proven survival benefit for metastatic prostate cancer, namely ADT and docetaxel. Now that there are multiple agents that can prolong survival in mCRPC, it is intriguing to consider the additive or even synergetic effect of adding multiple effective agents upfront in metastatic prostate cancer. Considering that the effect on the median overall survival of docetaxel deployed in hormone-sensitive metastatic prostate cancer is several-fold greater than its impact in mCRPC, it is attractive to consider clinical trials that further enhance the initial therapy for advanced prostate cancer.

Financial & competing interests disclosure

JN Graff has received research funding from Sanofi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.