In Hormone-Naive Metastatic Prostate Cancer, Should All Patients Now Receive Docetaxel? Yes; We Must Beware of Drawing Conclusions From a Subset Analysis

Medical or surgical castration (also termed androgen deprivation therapy [ADT]) has been the mainstay of therapy for men with newly diagnosed metastatic prostate cancer. However, with the exception of the potential clinical benefit of combined androgen blockade (CAB), which involves use of an anti-androgen together with ADT,[1] additional improvements in overall survival (OS) from first-line treatment of metastatic prostate cancer have proved difficult to achieve. Meanwhile, in men with metastatic castration-resistant prostate cancer (mCRPC), taxane-based chemotherapy agents (namely, docetaxel and cabazitaxel) have yielded significant improvements in survival in the setting of more advanced disease].[2,3] In the CHAARTED trial (Eastern Cooperative Oncology Group [ECOG] 3805), the investigators hypothesized that adding 6 cycles of docetaxel to ADT upfront in men with metastatic hormone-sensitive prostate cancer (mHSPC) would improve OS, putatively by eliminating nascent castration-resistant clones and by providing chemotherapy to men who might be unfit to receive it later in their disease course.

The CHAARTED study enrolled 790 men with newly diagnosed mHSPC and randomly assigned them to receive either ADT plus docetaxel (75 mg/m² every 21 days for 6 cycles) or ADT alone.[4] Patients were stratified on the basis of extent of metastases, age, ECOG performance status, use of CAB, use of skeletal-related event prophylaxis, and history of adjuvant ADT. High-volume disease was defined as the presence of visceral metastases, or ≥ 4 bone metastases (with at least 1 located beyond the axial skeleton).[5] At a planned interim analysis, the study demonstrated an impressive improvement in OS, with a hazard ratio of 0.61 (95% confidence interval [CI], 0.47–0.80; P = .0003); median survival was 57.6 months in the docetaxel-ADT arm, compared with 44.0 months in the ADT-alone arm. This 13.6-month prolongation of OS suggests a new standard of care for men with mHSPC who are good candidates for docetaxel chemotherapy (ie, who are “chemo-fit”).

In the forest plot analysis of the CHAARTED trial, the hazard ratios in all prespecified subgroups suggested a benefit from the upfront addition of docetaxel, of approximately similar magnitude across all strata, although the 95% confidence intervals did exceed 1.0 for patients with prior local therapy, non-white race, and low-volume metastatic disease. With respect to extent of metastases, men with high-volume disease demonstrated a clear improvement in median survival of 17.0 months, with a hazard ratio of 0.60 (95% CI, 0.45–0.81; P = .0006). Similarly, men with low-volume disease demonstrated a trend towards a comparable survival benefit, with a hazard ratio of 0.63 (95% CI, 0.34–1.17; P = .14), although this trend did not reach statistical significance. However, the data from the low-volume disease subset are too immature for any definitive conclusions to be formed either way about the added value of docetaxel in this setting. For example, while the number of deaths in the high-volume subset was 192/514 (37%), the number of deaths in the smaller low-volume subset was 45/276 (16%). Due to the more indolent natural history of the disease in the low-volume patients, longer follow-up will be required so that enough deaths can be observed to allow meaningful conclusions to be drawn. (Indeed, the survival curves in this subset do not begin to separate until after 24 months of follow-up.)Prolonged follow-up-to the point where at least 30% to 50% of patients in the subset have died-will be required in order to confidently demonstrate statistical significance (or lack thereof) in the low-volume-disease population.

While subgroup analysis may prove illuminating once the data are fully mature, it is important to note that CHAARTED was powered for the primary endpoint of seeing a survival difference in the overall patient population. Therefore, we would caution against basing clinical decisions on a subset analysis rather than on the overall analysis according to the primary aim of the study. It should be remembered that stratification by extent of disease, while certainly of prognostic significance,[5] has produced counterintuitive results in previous phase III studies of mHSPC. For example, in the Southwest Oncology Group (SWOG) 9346 trial that examined intermittent ADT vs continuous ADT in patients with mHSPC,[6] subset analyses seemed to suggest that men with extensive disease treated with continuous ADT had an inferior survival compared with those treated with intermittent ADT. Nevertheless, the overall conclusion of the SWOG 9346 study-that intermittent hormone therapy is not noninferior to continuous therapy in mHSPC patients-generally holds in clinical practice based on the primary analysis of this trial. Therefore, we would argue that the clinical interpretation of the CHAARTED results, in which the use of 6 cycles of docetaxel given together with first-line ADT resulted in a 39% relative reduction in the risk of death, should be applied to the entire study population of men with mHSPC, in accordance with the study’s primary objective.

What are the arguments against the use of early docetaxel therapy in all men with mHSPC? Some are highlighted here by Dr. Armstrong. Another plausible concern may be that the toxicities from early docetaxel use, particularly in men with low-volume disease, may outweigh any potential survival benefits. However, men treated with early docetaxel in the CHAARTED study appeared to tolerate the therapy considerably better than those treated with this drug in the castration-resistant setting. For example, 32% and 30% of men in the TAX 327 study[2] who were treated with every-3-week docetaxel experienced grade 3/4 neutropenia and grade 3/4 neuropathy, respectively, compared with 12% and 1% of the men in the CHAARTED study. Thus, administering chemotherapy early in these men may spare them some docetaxel-related toxicity later in the course of their disease, when it may be more difficult to tolerate.

Ultimately, while further follow-up will be enlightening, we believe that there is sufficient evidence now from the primary analysis of CHAARTED to justify the combination of docetaxel and ADT in all men with mHSPC.

Financial Disclosure:Dr. Antonarakis has served as a paid consultant to Sanofi Aventis. Dr. Suzman has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1. Prostate Cancer Trialists’ Collaborative Group. Maximum androgen blockade in advanced prostate cancer: an overview of the randomized trials. Lancet. 2000;355:1491-8.

2. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502-12.

3. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376:1147-54.

4. Sweeney C, Chen Y, Carducci MA, et al. Impact on overall survival with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer: an ECOG-led phase III randomized trial. J Clin Oncol. 2014;32(suppl):abstr LBA2.

5. Eisenberger MA, Blumenstein BA, Crawford ED, et al. Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med. 1998;339:1036-42.

6. Hussain M, Tangen CM, Berry DL, et al. Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med. 2013;368:1314-25.