‘Charting a new course for prostate cancer’ – currying favor for docetaxel in hormone-sensitive metastatic prostate cancer

Abstract

Docetaxel has an established role in the treatment of metastatic castrate-resistant prostate cancer. A number of recent treatments have been shown to improve the survival outcomes for this group of patients and many with improved toxicity profiles, bringing the role of docetaxel into question. We discuss the results and implications of the CHAARTED study that demonstrated a significant improvement in overall survival with docetaxel in metastatic hormone-sensitive prostate cancer.

Keywords::

• CHAARTED
• docetaxel
• hormone sensitive
• metastatic prostate cancer
• Sweeney

This year marks the 10-year anniversary of the landmark TAX327 trial that demonstrated a significant improvement in overall survival for docetaxel when compared to mitoxantrone (18.9 vs 16.5 months, p = 0.009) in patients with metastatic castrate-resistant prostate cancer (mCRPC) [1]. Docetaxel was the first drug to show a survival benefit in mCRPC and became established as the standard of care for men with mCRPC. Recently, the place of docetaxel in the treatment of mCRPC has come under question with several treatments and many with a lower toxicity profile showing a survival advantage. These include abiraterone, enzalutamide, sipuleucel-t, radium-223 and cabazitaxel (Table 1) [2–9].

Table 1. Summary of the evidence for the treatments that have been shown to prolong overall survival in patients with metastatic prostate cancer.

Setting	Trial treatment	Comparator treatment	Trial	Patients (n)	HR	Median OS (months)	OS benefit (months)	Ref.
mHSPC
	Docetaxel	Placebo	CHAARTED all patients: High volume:	790 514	0.61 0.60	57.6 vs 44.0 49.2 vs 32.2	13.6 17.0	[10]
mCRPC: Pre-docetaxel
	Docetaxel	Mitoxantrone	TAX327	1006	0.76	18.9 vs 16.5 19.2 vs 16.3	2.4 2.9^†	[1,13]
	Abiraterone	Placebo	COU-AA-302	1088	0.75 0.79	NR vs 27.2 35.3 vs 30.1	NR 5.2^†	[4,14]
	Enzalutamide	Placebo	PREVAIL	1717	0.70	32.4 vs 30.2 (estimated)	2.2 (estimated)	[5]
	Sipuleucel-T^‡	Placebo	Kantoff 2010	512	0.78	25.8 vs 21.7	4.1	[7]
mCRPC: Post-docetaxel
	Radium-223	Placebo	ALSYMPCA	921	0.70	14.9 vs 11.3	3.6	[8]
	Enzalutamide	Placebo	AFFIRM	1199	0.63	18.4 vs 13.6	4.8	[6]
	Cabazitaxel	Mitoxantrone	TROPIC	755	0.70	15.1 vs 12.7	2.4	[2]
	Abiraterone	Placebo	COU-AA-301	1195	0.65 0.74	14.8 vs 10.9 15.8 vs 11.2	3.9 4.6^†	[3,9]

^†Updated survival data.

^‡Sipuleucel-T trial also included post-docetaxel patients.

HR: Hazard ratio; mCRPC: Metastatic castrate-resistant prostate cancer; mHSPC: Metastatic hormone-sensitive prostate cancer; NR: Not reached; OS: Overall survival.

There has been an increased focus on improving outcomes by introducing treatments earlier in the disease course before castration resistance occurs. The CHAARTED study was designed for patients with hormone-sensitive prostate cancer (HSPC) to test the hypothesis that the addition of docetaxel to androgen deprivation therapy (ADT) would improve overall survival [10]. CHAARTED randomized 790 men, between July 2006 and November 2012, to receive either six cycles of docetaxel (75 mg/m² every 21 days) in combination with ADT or ADT alone. The patients were stratified by volume of disease with ‘high’ volume disease defined as visceral metastases and/or four or more bone metastases with at least one beyond the axial skeleton. The patients were also stratified based on age (≥70 vs <70 years), Eastern Cooperative Oncology Group performance status (0–1 vs 2), combined androgen blockade for >30 days (yes vs no), duration of prior adjuvant hormonal therapy (>12 vs ≤12 months) and concurrent bisphosphonate use (yes vs no). The primary endpoint was overall survival and the secondary endpoints were time to CRPC (radiographic, biochemical or symptomatic progression), time to clinical progression (radiographic or symptomatic progression), rate of prostate specific antigen (PSA) <0.2 ng/ml at 6 and 12 months, treatment tolerability and quality of life outcomes.

The primary endpoint was met with an improvement in median overall survival of 13.6 months (57.6 vs 44.0 months, hazard ratio [HR]: 0.61, p = 0.0003) and a remarkable 17 months (49.2 vs 32.2 months, HR: 0.60, p = 0.0006) in ‘high’ volume patients receiving docetaxel (n = 514 [65% of all patients]). In the patients with low volume disease overall survival has not yet been reached for either group, HR: 0.63 (95% CI [confidence interval]: 0.34–1.17, p = 0.1398). The combination of docetaxel and ADT also met all the secondary endpoints with an increase in the number of patients with PSA <0.2 ng/ml at 6 months (27.5 vs 14%, p < 0.0001) and 12 months (22.7 vs 11.7%, p < 0.0001) as well as an increased median time to CRPC (20.7 vs 14.7 months, p < 0.0001) and increased median time to clinical progression (32.7 vs 19.8 months, p < 0.0001). At the time of analysis, of the 174 who progressed after ADT alone 129 (74%) had received docetaxel for CRPC disease. In the ADT plus early docetaxel group 49 of 145 (33%) patients who had progressed were retreated with docetaxel. Treatment with abiraterone or enzalutamide beyond progression was similar in both arms and therefore unlikely to impact on survival outcomes. The majority of patients (87.5%) completed all six cycles of docetaxel, which was reasonably well tolerated. Grade 3 or 4 neutropenia, anemia, thrombocytopenia and febrile neutropenia were seen in 12, 1, <1 and 6% of patients, respectively. There was one treatment-related sudden death.

CHAARTED is not the only study to have examined the role of docetaxel combined with ADT in metastatic HSPC. Gravis and colleagues investigated the role of docetaxel with ADT in the Phase III trial GETUG-AFU 15 [11]. They randomized 395 patients to receive ADT plus docetaxel (75 mg/m² every 21 days for nine cycles) or ADT alone. The primary endpoint was overall survival with 80% power to detect a HR of 0.62 for death. A total of 83 patients (22%) were classified as having a poor prognosis as per the Glass criteria (defined as the presence of appendicular disease, a performance status ≥1 and PSA ≥65 ng/ml) [12]. Median overall survival was 58.9 months in the ADT plus docetaxel group and 54.2 months in the ADT alone group although this was not statistically significant (HR: 1.01; 95% CI: 0.75–1.36; p = 0.955). No significant difference in overall survival was seen in the different prognostic groups although the trial was not powered to detect a difference. It is important to note that 62% of patients in the ADT alone group and 28% in the ADT plus docetaxel group received docetaxel at progression. Thirty-two percent of patients receiving chemotherapy developed grade 3 or 4 neutropenia with 7% experiencing febrile neutropenia. The median number of docetaxel cycles was eight with 48% of patients receiving the nine planned cycles of chemotherapy. Four treatment-related deaths were reported in the docetaxel group due to febrile neutropenia, neutropenia with infection, multiorgan failure, and pulmonary embolism. The authors concluded that the addition of docetaxel to ADT does not improve overall survival compared to ADT alone in HSPC. However, the secondary endpoints were met with prolongation of both biochemical progression-free survival (22.9 vs 12.9 months; HR: 0.72, 95% CI: 0.57–0.91; p = 0.005) and clinical progression-free survival (23.5 vs 15.4 months; HR: 0.75; 95% CI: 0.59–0.94; p = 0.015) seen in the group given ADT plus docetaxel. Based on a subgroup analysis, patients in the low and intermediate prognostic groups seemed to benefit more (HR: 0.58 and 0.59, respectively) than those in the high prognostic group (HR: 0.82).

How can these differing results be explained? The differences observed may be due to the underlying prognosis of the patients in each study. The median overall survival of the ADT alone group in the CHAARTED trial was 44 months (32.2 months in the high volume group) compared to 54.2 months in the GETUG trial. Although there is no direct equivalent in the GETUG trial, 22% of patients were in a poor prognostic subgroup that had an overall survival of 36.6 months. This is similar to the prognosis of the high volume group in CHAARTED that received ADT alone but in CHAARTED 65% of patients were in the high volume group. Although the GETUG trial did not show a survival benefit with the addition of docetaxel, it did show benefit in terms of delaying biochemical and clinical progression that were of similar magnitude to that seen in the CHAARTED study. Although secondary endpoints, they give a strong signal for the efficacy of docetaxel in this population of patients.

Based on the results presented from CHAARTED, identification of patients with ‘high’ volume disease is critical, as this defines benefit from early chemohormonal therapy. It is unclear whether this is the most effective way of assessing the overall burden of disease in patients with prostate cancer. However, the CHAARTED trial has used its definition for ‘high’ volume of metastatic disease prospectively and a clear difference in overall survival is seen when compared to patients with ‘low’ volume disease. It will be of interest to see if other prognostic factors such as baseline PSA, circulating tumor cells, circulating free tumor DNA, molecular and genomic analyses (such as PTEN-loss) or even novel imaging techniques might play a role in the risk stratification process of prostate cancer patients. Further studies are required to determine the optimal way of predicting benefit from early chemohormonal therapy.

The results from the CHAARTED trial are practice changing and move docetaxel into the HSPC setting, for patients with high volume disease. This will radically change the treatment paradigm for metastatic prostate cancer and raises several questions regarding subsequent therapies. For example, will patients treated with ‘early’ docetaxel benefit from re-treatment upon progression? Given the median time to progression for docetaxel plus ADT, this is a likely clinical scenario. With several active agents for CRPC (Table 1), activity and toxicity of each of these drugs post docetaxel given with ADT will be critical in defining the most active and best tolerated sequence of treatment.

The results from CHAARTED show an improvement in overall survival that has been never seen in metastatic prostate cancer trials and is rarely seen in clinical trials for metastatic solid malignancies. CHAARTED clearly demonstrates that the addition of docetaxel to ADT in patients with high volume metastatic HSPC was well tolerated and resulted in a large improvement in overall survival. We await with interest the results of other studies investigating docetaxel and other agents in this setting such as the Medical Research Council STAMPEDE study with a specific focus on the metastatic study population. As yet, patients are selected by clinical characteristics of ‘high volume’ disease although ultimately we would like to have predictive biomarkers to further improve patient outcomes. CHAARTED has unequivocally shown that, for selected patients, large gains in survival are achievable and these results will encourage others to strive for even greater improvements for patients with metastatic prostate cancer.

Financial & competing interests disclosure

S Chowdhury, J Staffurth, Z Malik and C Sweeney are speakers for and advisory board members of 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.

No writing assistance was utilized in the production of this manuscript.