Docetaxel in prostate cancer: a familiar face as the new standard in a hormone-sensitive setting

Abstract

The increasing knowledge of prostate cancer is leading to many questions about its natural history and to reconsider conventional therapeutic strategies. Androgen ablation therapy has been the standard therapy in the advanced setting. Although docetaxel has demonstrated increased survival in patients with metastatic prostate cancer who had progressed to hormone treatments, due to its potential toxicity the role of chemotherapy has been relegated to patients who were symptomatic or who had high tumor burden. Several studies have assessed whether docetaxel could have a role in hormone-sensitive disease or even in earlier stages with no distant metastases. In the CHAARTED and STAMPEDE studies, docetaxel provides an unprecedented increase in overall survival (OS). This review summarizes the evidence behind the paradigm shift to strengthening docetaxel as a new standard of treatment that prolongs survival in earlier stages of prostate cancer.

Introduction

It was estimated that about 25,000 men would die from metastatic prostate cancer in 2014 in the United States, leading to the main cause of male cancer death [Siegel et al. 2014]. Despite the fact that prostate cancer is the most prevalent tumor in men worldwide [Fitzmaurice et al. 2015], it was only recently that we are becoming aware of its natural history, how it has changed over recent years and how it will change in the future based on our diagnostic and therapeutic interventions. The arrival of new drugs, mainly in the castration-resistant prostate cancer (CRPC) context, has promoted the interest in this pathology and in the knowledge based on the development of different studies at all levels that question the management paradigm and propose new approach strategies based on these recent findings.

Prostate cancer is typically diagnosed at early stages but some patients develop metastases after local treatment with radiotherapy and/or surgery. Since the 1940s, the initial management of advanced prostate cancer has involved androgen deprivation therapy (ADT) [Huggins and Hodges, 1941]. In spite of the fact that more than 90% of patients initially responding to ADT, the disease inexorably evolves towards a situation called ‘castration-resistant’. Patients with metastatic hormone-sensitive prostate cancer (mHSPC) treated with ADT have a median overall survival (OS) of around 49 months [Tangen et al. 2012].

More than 10 years ago, docetaxel provided a significant advantage in CRPC survival [Tannock et al. 2004]. In the metastatic CRPC (mCRPC) state the TAX-327 study showed that the survival benefit of docetaxel, when administered every 3 weeks (D3P) compared with mitoxantrone (MP), persisted with extended follow up (p = 0.004). Median OS was 19.2 months [95% confidence interval (CI), 17.5–21.3 months] in the D3P arm and 16.3 months (95% CI, 14.3–17.9 months) in the MP arm. More patients survived 3 years in the D3P arm (18.6%) compared with the MP arm (13.5%) [Dominik et al. 2008]. However, due to its potential toxicity, treatment with docetaxel was relegated to mCRPC patients who have progressed after ADT and presented symptoms arising from the progression of the disease.

Even though the mechanism of action of the taxanes is not fully understood, part of their effectiveness resides in their interaction with androgen signaling in prostate cancer cells at both the cytoplasmic level and the nuclear level, affecting transcriptional regulators of androgen-responsive gene expression [Fitzpatrick and De Wit, 2014]. However, part of the antitumor activity of the taxanes may not be due to an androgen-dependent mechanism.

The advance of molecular knowledge in recent decades, primarily due to high-throughput molecular profiling studies, has led us to understand that cancer is a heterogeneous entity. Considering prostate cancer as a heterogeneous entity, where androgen-dependent and independent clones cohabitate, a strategic option should be to use a combination of drugs that act on the various populations in earlier stages and prevent the development of resistance.

Metastatic hormone-sensitive prostate cancer

Based on the hypothesis that we have previously mentioned, an early chemotherapy might improve the overall outcome of patients with mHSPC by attacking cells that are androgen-independent or androgen-sensitive before they become resistant or grow in volume. Furthermore, this strategy allows an earlier access of patients, and in a better condition, to more recent treatments that have demonstrated to increase survival in the post-docetaxel setting.

Several studies were designed with this rationale, to verify the role of chemotherapy on hormone-sensitive disease in the advanced setting. Results from three phase III clinical studies that evaluated the role of docetaxel in mHSPC, have been recently reported: CHAARTED study (E3805) [Sweeney et al. 2015], GETUG-AFU 15 [Gravis et al. 2013; Gravis et al. 2015] and the STAMPEDE study [James et al. 2016a; James et al. 2016b].

CHAARTED study

The E3805 (Chemo-Hormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer; CHAARTED) study compared the effect of adding six cycles of docetaxel (75 mg/m²) (experimental arm) or not (control arm) at the time of commencement of the standard ADT in mHSPC patients, with the main objective of improving OS [Sweeney et al. 2015]. The results of the study provided practice-changing evidence to the initial approach to HSPC patients.

The CHAARTED study was initially planned for patients with ‘high-volume’ metastatic disease (four or more bone metastases with at least one beyond the pelvis and vertebral column or visceral metastases), because this situation was associated with shorter survival and it was assumed that these kind of patients would benefit more from the addition of chemotherapy. Later on, the protocol was amended to allow the inclusion of 30% of patients with ‘low-volume’ disease in the study, and the sample size was recalculated to maintain an 80% power (one-sided alpha = 2.5%), to detect a 33% improvement in the median OS.

A total of 790 men were recruited between July 2006 and November 2012. A planned interim analysis was made in October 2013, assessing about 53% of the study data, and meeting the criteria for significance. Patient characteristics were well balanced between the two study arms and, notably, approximately two-thirds of patients in each arm were classified as having high-volume metastasis. About three-quarters of men in each arm had received no prior local treatment. With a median follow up of 28.9 months, the median OS was 57.6 months in the docetaxel plus ADT arm and 44.0 months in the ADT arm [hazard ratio (HR) 0.61; 95% CI (0.47, 0.80); p = 0.0003]. In patients with high-volume disease, a difference of 17 months [HR: 0.60; 95% CI (0.45, 0.81); p = 0.0006] was observed in the median OS with docetaxel plus ADT compared with ADT alone (49.2 versus 32.2 months, respectively). In patients with low-volume disease, median OS had not been reached at the time of the analysis. As expected, a majority of patients who relapsed in the control arm received docetaxel after progression, and there were no meaningful differences between both arms in the administration of other treatments that could have affected OS.

The regimen of docetaxel plus ADT was beneficial in all subgroups analyzed. Median time to clinical progression was greater in the docetaxel plus ADT arm than in the ADT-only arm [32.7 versus 19.8 months, respectively; HR: 0.49; 95% CI (0.37, 0.65); p < 0.0001]. Similarly, the median time to CRPC was higher in the docetaxel plus ADT arm [20.7 versus 14.7 months in the ADT-alone arm; HR: 0.56; 95% CI (0.44, 0.70); p < 0.0001]. In addition, all secondary endpoints were significantly improved in the docetaxel-containing arm compared with hormone therapy alone. The percentage of patients with a serum prostate-specific antigen (PSA) level <0.2 ng/ml at 6 and 12 months in the docetaxel-containing arm (27.5 and 22.7%, respectively) was higher than for the ADT-alone arm (14 and 11.7%, respectively). Median time to castrate resistance (20.7 versus 14.7 months) and median time to clinical progression (defined as symptomatic or radiological progression; 32.7 versus 19.8 months, respectively) were longer in the experimental arm when compared with the control arm (HR: 0.49; p < 0.0001). A total of 74% of patients completed the planned six cycles of therapy. Overall, 6% of patients receiving the chemo-hormonal regimen experienced febrile neutropenia, 1% experienced significant effects on sensory nerves and 1% on motor nerves, and 1 of the 397 patients who received early docetaxel died as a result of treatment. The main cause of death was due to prostate cancer [n = 84 patients (83.2%) for the ADT plus docetaxel arm and n = 112 (83.6%) for the ADT-alone arm].

GETUG-AFU 15 study

The potential use of docetaxel in the context of hormone-sensitive disease has also been explored in the GETUG-AFU 15 study [Gravis et al. 2013; Gravis et al. 2015]. GETUG-AFU 15 was a randomized, open-label, phase III study in patients with newly diagnosed mHSCP. Between October 2004 and December 2008, 192 patients were randomly assigned to receive ADT plus docetaxel and 193 to receive ADT alone. After a median follow up of 82.9 months there was no statistically significant difference in the primary endpoint of OS between the two treatment groups. Patients were allocated in a 1:1 ratio and a dynamic minimization was used to minimize the imbalance of three criteria, including Glass prognostic groups (good, intermediate and poor prognostic). After a median follow up of 50 months, the median OS achieved in the docetaxel plus ADT arm was 58.9 months compared with 54.2 months in the ADT arm [HR: 1.01; 95% CI (0.75, 1.36); p = 0.955]. Median biochemical progression-free survival (bPFS) and clinical progression-free survival (cPFS) were significantly longer in the group that received docetaxel plus ADT.

Gravis presented an update analysis for OS at the 2015 Genitourinary Cancers Symposium [Gravis et al. 2015]. After a median follow up of 82.5 months, the median OS was 60.9 months in the docetaxel plus ADT arm and 46.5 months in the ADT arm [HR: 0.9; 95% CI (0.7, 1.2); p = 0.44]. A retrospective assessment of tumor volume was also reported, using the same definition than in the CHAARTED study (‘high-volume’ metastatic disease was defined as four or more bone metastases with at least one beyond pelvis and vertebral column and/or visceral metastases). The median OS achieved in the ‘high-volume’ group of patients was 39 months for those in the docetaxel plus ADT arm and 35.1 months for those in the ADT arm [HR: 0.8; 95% CI (0.6, 1.2); p = 0.35], and in the ‘low-volume’ group of patients was 83.1 months for those in the docetaxel plus ADT arm and was not reached in the ADT arm [HR: 1.0; 95% CI (0.6, 1.5); p = 0.87].

The median number of docetaxel cycles administered at the GETUG-15 study was 8 (range: 0–9), and almost half of patients (48%; n = 93 patients) received the 9 planned cycles. A total of 72 serious adverse events were reported in the ADT plus docetaxel group, and neutropenia (n = 40; 21%) was the most commonly reported one.

CHAARTED versus GETUG-15

Despite the fact that both studies are quite similar in several aspects, namely the hormone-sensitive setting or the prior treatment with ADT (allowed in both studies as long as the treatment had been used in the adjuvant setting and for less than 2 years), there are subtle differences between the CHAARTED and GETUG-15 studies in terms of the study design and in the patient population recruited (differences in the baseline patient characteristics and in the systemic treatments received after progression; Table 1), that may have led to different clinical outcomes. The plasma levels of PSA at study entrance were almost twice in the CHAARTED study than in the GETUG-15 study, and around 65% of the patients in the CHAARTED study had a high volume of metastases while only 48% in the GETUG-15 study had high volume disease. In addition, 60.7% of the patients in the docetaxel + ADT and 61.8% in the ADT-alone arm recruited for the CHAARTED study had a Gleason score ⩾8 versus only 55% in the docetaxel + ADT arm and 59% in the ADT-alone arm for the GETUG-15 study. These data support the idea that the CHAARTED study included patients with worse prognosis than those recruited for the GETUG-15 study.

Table 1.

Patients baseline characteristics in the CHAARTED, GETUG-15 and STAMPEDE studies (no direct comparison).

	CHAARTED study [Sweeney et al. 2015]		GETUG-15 study [Gravis et al. 2013, 2015]		STAMPEDE study [James et al. 2016a, 2016b]
	ADT + Doc (n = 397)		ADT + Doc (n = 192)		ADT + Doc (n = 592)
	n	%	n	%	n	%
Age (years)
Median age (range)	64 (36–88)		63 (46–79)*****		65 (40–81)
ECOG
0–1	391	98.5	192	100	586	99
2	6	1.5	—	—	6	1
Initial Gleason score
⩾7	117	29.5	84	45	110	19
8–10	241	60.7	103	55	476	74
Unknown	39	9.8	—	—	46	8
PSA (ng/ml)
Median	50.9****		26.7		70
Range	0.2–8540.1		0.05–2170		1–9999
Metastasis
Metastatic	298**	75**	128	67*	362	61
Visceral metastases	57	14.4	31	16	19	3
Volume of metastases
Low	134	33.8	100	52	NA	NA
High	263	66.2	92	48	NA	NA
Therapies at progression
Docetaxel	54	13	54	28	44	14
Cabazitaxel	57	13.7	3	2	22	7
Abiraterone/enzalutamide	105***	25.2	28	15	114	36
Sipuleucel-T	22	5.3	0	0	0	0
Others	178	42.8	106	55.5	6	2

^*Metastatic at diagnosis.

^**Tannock (abstract discussion ASCO 2015).

^***2 patients may have had placebo on trial.

^****At start of ADT.

^*****Long-term analysis of the GETUG-AFU 15 phase III trial [Gravis, 2015].

ADT, androgen deprivation therapy; Doc, docetaxel; ECOG, Eastern Cooperative Oncology Group Score; PSA, prostate-specific antigen; NA, not available.

OS was the primary endpoint for both studies, but the estimated sample size in the GETUG-15 study was of 378 patients (to demonstrate a HR for superiority of 0.62) while in the CHAARTED study it was of 780 patients (to demonstrate a benefit in terms of HR for death of 0.67). In the GETUG-AFU 15 study a much higher rate of survival than that expected was found in the ADT-alone group, and this finding could be due to the sample size calculation that was too low to show any differences in survival. The patients that were randomized to the chemotherapy arm in the CHAARTED study received up to six cycles of docetaxel 75 mg/m² every 21 days, while in the GETUG-15 study the patients allocated in the docetaxel-containing arm received up to nine cycles.

STAMPEDE study

The Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) study [James et al. 2016a; James et al. 2016b] is the third and the largest of these academic studies that have tried to answer the same question. STAMPEDE is a randomized controlled study using a novel multi-arm, multi-stage design, whose control arm is the standard ADT treatment.

A total of 2962 patients were randomly assigned to four groups between October 2005 and March 2013. Allocation was in a 2:1:1:1 ratio to standard of care only (ADT alone; n = 1184), standard of care plus zoledronic acid (ZA; ADT + ZA; n = 593), standard of care plus docetaxel (Doc; ADT + Doc; n = 592), or standard of care plus zoledronic acid and docetaxel (ADT + ZA + Doc; n = 593). Newly diagnosed prostate cancer was considered when any of the following situations occurred: to be node positive or to present two or more of the following conditions: stage T3/4, PSA >40 ng/ml and Gleason 8–10. Newly diagnosed metastatic prostate cancer patients were also included. The main endpoint was OS, while failure-free survival (FFS) was considered a secondary endpoint. FFS was defined as biochemical PSA progression (50% above the nadir for those with a >50% decline), clinical or radiological progression or death from disease. Other secondary endpoints included toxicity, skeletal-related events and cost-effectiveness.

A total of 61% of the total study population were metastatic and the remaining 39% had locally advanced non-metastatic prostate cancer. Results from the four treatment arms (ADT alone, ADT + Doc, ADT + ZA and ADT + ZA + Doc) observed that after a median follow up of 43 months, OS in the experimental arm with docetaxel were 10 months better than in the control arm [81 versus 71 months, HR: 0.78; 95% CI: (0.66, 0.93); p = 0.006]; in the metastatic subgroup the difference observed between the experimental and the control arm was more than double with an improvement of 15 months [60 versus 45 months; HR: 0.76 [95% CI (0.62–0.92)]; p = 0.005]. A reduction of skeletal events was observed in the group receiving docetaxel, with a HR: 0.60 [95% CI (0.62–0.92)]; p = 0.127 × 10^–5) in all patients (with or without metastasis) [James et al. 2016b].

Meta-analysis of GETUG-15, CHAARTED and STAMPEDE studies

A systematic review and meta-analysis of the available randomized studies was recently reported by the UK Medical Research Council Clinical Trials Unit at University College London (UCL), UK [Vale et al. 2015] about treatment options for prostate cancer. In the metastatic setting, they analyzed the results of three studies (GETUG-15, CHAARTED and STAMPEDE). A total of 2993 patients were analyzed for OS, obtaining a HR of 0.77 [95% CI (0.68–0.87)] with a 10% absolute improvement in survival at 4 years. For FFS, with 2993 patients analyzed, HR was 0.64 (95% CI 0.58–0.70), with a 15% of absolute reduction in failure at 4 years.

The toxic effects were higher in the combination arm with docetaxel. Grade 3–5 effects in the patients that presented any adverse effects were about 50% in the docetaxel arms versus 30% in the non-docetaxel ones. These effects were manageable and practically evened out after 1 year of treatment. The addition of the zoledronic acid did not provide an advantage by itself. See Tables 1 to 3 for details on the baseline characteristics of the patients (Table 1), the efficacy data (Table 2) and the toxicity data (Table 3) resulting from the GETUG-15, CHAARTED and STAMPEDE studies.

Table 3.

Toxicity from the CHAARTED, GETUG-15 and STAMPEDE studies (no direct comparison).

		CHAARTED STUDY [Sweeney et al. 2015]	GETUG-15 STUDY [Gravis et al. 2013, 2015]	STAMPEDE STUDY [James et al. 2016a, 2016b]
		ADT + Doc (n = 397)	ADT + Doc (n = 192)	ADT + Doc (n = 579)
Planned cycles with Doc		6	9	6
Any events grade >3 (%)		29.6	—	52
Non-hematology toxicity	Allergic reaction	2.1	—	—
(Grade 3–5) (%)	Fatigue	4.1	7	—
	General disorder	—	—	7
	Endocrine disorder	—	—	10
	Diarrhea	1.0	<1	—
	Stomatitis	0.5	<1	—
	Gastrointestinal disorder	—	—	8
	Neuropathy-motor	0.5	—	—
	Neuropathy-sensory	0.5	2	—
	Musculoskeletal disorder	—	—	6
	Thrombo-embolism	0.8	—	—
	Renal disorder	—	—	4
	Nail changes	—	3	1
	Sudden death	0.3	—	—
	Respiratory disorder	—	—	5
	Cardiac disorder	—	—	3
	Nervous system other (including peripheral neuropathy)	—	—	3
Hematology toxicity	Anemia	1.3	2	—
(Grade 3–5) (%)	Thrombocytopenia	0.3	<1	—
	Neutropenia	12.1	32	12
	Febrile neutropenia	6.1	7	15
	Infection with neutropenia	2.3	2	—

ADT, androgen deprivation therapy; Doc, docetaxel.

Table 2.

Efficacy results from the CHAARTED, GETUG-15 and STAMPEDE studies (no direct comparison).

	CHAARTED study [Sweeney et al. 2015]	GETUG-15 study [Gravis et al. 2013, 2015]	STAMPEDE study [James et al. 2016a, 2016b]
	ADT + Doc (n = 397)	ADT + Doc (n = 192)	ADT + Doc (n = 592)
OVERALL SURVIVAL
OS (months)			81
HR			0.78 (0.66–0.93)
p value			0.006
OS M1 (months)	57.6	60.9****	60
HR	0.61 (0.47–0.80)	0.9 (0.7–1.2)****	0.76 (0.62–0.92)
p value	<0.001	0.44****	0.005
OS by extent of metastasis
OS low volume (months)	NR	83.1****	—
HR	0.60 (0.32–1.13)	1.0 (0.6–1.5)****	—
p value	0.11	0.87****	—
OS high volume (months)	49.2	39****	—
HR	0.60 (0.45–0.81)	0.8 (0.6–1.2)****	—
p value	<0.001	0.35****	—
Progression-free survival
PFS	33.0*	23.5**	37***
HR	0.61 (0.50–0.75)	0.75 (0.59–0.94)	0.61 (0.53–0.70)
p value	<0.001	0.015	<0.0000000004

^*Time to clinical progression.

^**Clinical progression-free survival (cPFS).

^***Failure-free survival (FFS) (First of: PSA failure, local failure, lymph node failure, distant metastases, prostate cancer death).

^****Long-term analysis of the GETUG-AFU 15 phase III trial [Gravis et al. 2015].

ADT, androgen deprivation therapy; cPFS, clinical progression-free survival; Doc, docetaxel; FFS, failure-free survival; HR, hazard ratio; NR, not reached; OS, overall survival; PFS, progression-free survival; PSA, prostate-specific antigen.

High-risk localized prostate cancer

As we have previously hypothesized, early chemotherapy might improve the overall outcome of patients with mHSPC, therefore patients with high-risk localized prostate cancer could potentially benefit from earlier chemotherapy.

Several prospective randomized clinical studies had evaluated the use of neoadjuvant (Table 4) and adjuvant chemotherapy in high-risk patients (Table 5).

Table 4.

Prospective clinical studies using neoadjuvant chemotherapy in high-risk patients.

Study name	Phase	Number of patients	Setting	Intervention	Status
GETUG-12 [Fizazi et al. 2015]	Phase III	n = 413	Neoadjuvant high-risk	ADT ± DE	Reported
DANA FARBER [ClinicalTrials.gov identifier: NCT00116142]	Phase III	n = 350 (planned)	Neoadjuvant high-risk	ADT + D —> RT + D versus ADT + RT	Ongoing
CALGB 90203* [Eastham et al. 2003; Pietzak and Eastham 2016]	Phase III	n = 780	Neoadjuvant high-risk	P ± ADT + D	Fully accrued
TAX3503 [Morris et al. 2015]	Phase III	n = 413	Neoadjuvant high-risk	ADT ± D	Ongoing
Zhao study [Zhao et al. 2015]	Phase II	n = 28	Neoadjuvant high-risk	D before RP	Reported

ADT, androgen deprivation therapy; bPFS, biochemical progression-free survival; D, docetaxel; DE, docetaxel + estramustine; P, prednisone; RP, radical prostatectomy; RT, radiotherapy.

^*CALGB 90203 began recruiting patients in 2007 with the goal of accruing 750 patients, and as of October 2015, more than 780 patients have been enrolled and accrual has closed. The primary endpoint of 3-year bPFS is expected to be reported in June 2018.

Table 5.

Prospective randomized clinical studies using adjuvant chemotherapy in high-risk patients.

Study name	Phase	Number of patients	Setting	Intervention	Status
TAX3501 [Schweizer et al. 2013] (1)	Phase III	n = 228 (1695 planned)	Adjuvant high-risk	ADT ± D	Early accrual termination
RTOG 9902 [Rosenthal et al. 2009] (2)	Phase III	n = 397	Adjuvant high-risk	ADT + RT + Pa	Early accrual termination
S9921 [Dorff et al. 2011] (3)	Phase III	n = 983 (1360 planned)	Adjuvant high-risk	ADT ± M-P	Early accrual termination
ADPRO SPCG 12 *	Phase III	n = 154 (396 planned)	Adjuvant high-risk	D versus O	Accrual complete
VA CSP 553 [Montgomery et al. 2008]	Phase III	n = 65 (636 planned)	Adjuvant high-risk	D + P versus O	Ongoing
AdRad**	Phase III	n = 9 (924 planned)	Adjuvant high-risk	ADT ± D	Ongoing
Gutilla study [Guttilla et al. 2014]	Phase II	n = 35	Adjuvant high-risk	RT ± P—> ADT + D	Reported
RTOG0621***	Phase II (single arm)	n = 76	Adjuvant high-risk	ADT + RT + D	Ongoing
RTOG0521 [Sandler et al. 2015]	Phase III	n = 612	Adjuvant high-risk	ADT + RT ± D	Ongoing
QRT SOGUG STUDY [Galceran et al. 2015]	Phase IIb	n = 130	Adjuvant high-risk	ADT + RT ± D	Ongoing

ADT, androgen deprivation therapy; D, docetaxel; M, mitoxantrone; O, observation; P, prednisone; Pa, paclitaxel; PFS, progression-free survival; RT, radiotherapy.

^*[ClinicalTrials.gov Identifier: NCT00376792; ^**ClinicalTrials.gov Identifier: NCT00653848;]

^***[ClinicalTrials.gov Identifier: NCT00528866].

(1) This trial was terminated prematurely because of enrollment challenges, leaving it underpowered to detect differences in PFS.

(2) The trial was closed prematurely in 2004 due to substantial toxicity (thromboembolic events) observed in the experimental arm.

(3) This was the largest accrued adjuvant chemo study although this trial was closed to accrual in January 2007 due to the development of leukemia in three patients treated with mitoxantrone. Follow up is ongoing.

Radical prostatectomy and radiation therapy are considered as the standard treatment for most patients at this stage. However, a significant subgroup of patients progress after these strategies. To demonstrate the efficacy (particularly the benefit in terms of OS) of any new drug in this stage of disease is complicated. The unclear definition of high-risk localized disease, among other difficulties, led to the closure of several studies like TAX3501 [Schweizer et al. 2013] or RTOG 9902 [Rosenthal et al. 2009]. Both studies illustrated several difficulties involved in conducting postoperative adjuvant systemic studies in men with high-risk prostate cancer, namely a lack of consensus regarding patient selection and treatment, the need for long follow-up time and for a long-term research support, and the high toxicity that was observed with some drug combinations.

The D’Amico classification [D’Amico et al. 1998] considers that a patient is at high risk if he presents with localized prostate cancer at a clinical stage ⩾T2c, has a Gleason score 8–10, or a PSA level greater than 20 ng/ml.

On the other hand, National Comprehensive Cancer Network (NCCN) guidelines [NCCN, 2016], consider that a patient is at high risk if he has localized prostate cancer at a stage ⩾T3a, a Gleason score 8–10, or a PSA level greater than 20 ng/ml.

Neoadjuvant chemotherapy with docetaxel has been assessed in numerous studies (Table 4). The preliminary results of the phase 3 randomized GETUG-12 study [Fizazi et al. 2015], have shown a benefit in the 8-year relapse-free survival for the experimental group (ADT + Doc + estramustine). According to the high-risk criteria defined by the D’Amico classification and the NCCN guidelines, patients with stage T3–T4 or high PSA concentration, benefited substantially from chemotherapy. However, although not considered in the high-risk classifications, patients with a Gleason score <8 also derived a greater benefit in terms of relapsed-free survival from chemotherapy versus ADT alone (HR: 0.54 [95% CI (0.36–0.81)]; p = 0.047) than those with a higher Gleason score (HR: 1.02 [95% CI (0.68–1.54)]; p = 0.047). The authors considered that these data might be due to a differential effect of taxanes on androgen receptor trafficking according to the Gleason score, an insufficient effect of four cycles against undifferentiated tumors, or a more potent effect of estramustine against well-differentiated tumors. The publication of the OS data for this study are still pending, which arguably is the most important piece of information to come out of this study.

The results of a phase II study [Zhao et al. 2015] of neoadjuvant chemotherapy with docetaxel before radical prostatectomy, were also favorable for the experimental group, although conclusions should be made with caution as it was a small sized study without a comparator group.

Both studies suggest the potential of prolonged survival by neoadjuvant docetaxel in patients with locally advanced prostate cancer who have high-risk factors. This hypothesis will need to be validated in further randomized clinical studies, like the Dana Farber study [ClinicalTrials gov identifier: NCT00116142] or the CALGB90203 study [ClinicalTrials gov identifier: NCT00430183] which are currently ongoing.

Adjuvant chemotherapy with docetaxel has been studied in numerous studies as well (Table 5). The results of TAX3503, RTOG0521, and QRT SOGUG studies, that were presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting and the 2015 Genitourinary Cancers Symposium show the benefit of chemotherapy. In our opinion, improvement in OS was observed with adjuvant chemotherapy for localized, high-risk, hormone-sensitive prostate cancer. PSA failure differences were small, so further considerations are needed.

In the phase III TAX3503 study [Morris et al. 2015], 413 patients were enrolled. After a median follow-up time in the intention-to-treat population of 31.5 months, the median PFS was 25.6 [95% CI (2.0–27.8)] in the group receiving docetaxel and 23.1 (22.6–25.0) in the study group without docetaxel. The 3-year PFS probability was 0.18 (0.13–0.25) for the ADT + Doc group and 0.10 (0.05–0.16) for ADT alone, respectively. However, the difference in PFS was small, maybe due to a short follow-up period.

In the phase III RTOG0521 study [Sandler et al. 2015], 612 patients were enrolled but only 563 patients were eligible for analysis. More than half of the patients (53%) had a high-risk category (Gleason⩾9, PSA⩾150, any T-stage). The patient median follow-up period was six years. The main endpoint for efficacy was the OS. The 4-year OS was 89% in the group not receiving docetaxel and 93% in the group receiving docetaxel (HR: 0.07; 90% CI 0.51–0.98; p = 0.04). The 6-year disease free survival without docetaxel was 65% versus 55% with docetaxel (HR: 0.76; 95% CI 0.58–0.99), and the 6-year biochemical failure was 74% versus 66% (HR: 0.81; 85% CI 0.58–1.11), respectively. The development of distance metastasis over time was lower in the group of patients receiving docetaxel compared with the ADT group. A total of 86% of patients received treatment with chemotherapy, and dose modification/delays were not necessary in 82% patients.

In the phase IIb QRT SOGUG study [Galceran et al. 2015], 30 patients were enrolled. A total of 75.7% of patients received the planned nine treatments of docetaxel, and were followed-up for a median of 29.6 months. Preliminary safety results show that concurrent weekly docetaxel can be safety administered with standard doses of radiotherapy and standard ADT.

Of note, we mention the results of the efficacy data observed in the M0 patients in the GETUG-12, RTOG 0521 and STAMPEDE studies that were assessed in the systematic review and meta-analysis presented by Vale and colleagues [Vale et al. 2015]. In the M0 setting, a potential improvement of 5% in survival (in terms of OS) at 4 years was observed in 2120 patients, with a HR: 0.87 (95% CI 0.69–1.09) when docetaxel was combined with ADT. For FFS, they analyzed the results of four studies (GETUG-12, RTOG 0521, STAMPEDE and TAX3501) in a total of 2348 patients, obtaining a HR: 0.70 (95% CI 0.61–0.81), with an 8% absolute reduction in failure at 4 years. We agree with Vale and colleagues that more evidence is needed to assess survival in M0 patients.

Discussion

Prostatic cancer is a heterogeneous disease, where a majority of androgen-dependent cells coexist with other non-androgen-dependent cells from the beginning of the malignization [Beltran et al. 2011]. ADT has classically been the most effective treatment for advanced disease. It is associated with a median PFS of about 2 years, but its results are in part dependent on the tumor burden of the patient. Docetaxel has been demonstrated to increase the survival of patients with mCRPC, although the benefit obtained in median OS over its comparator (mitoxantrone) was no more than a few months. Until recently, treatment with docetaxel was relegated to mCRPC patients who have progressed after ADT.

The GETUG-AFU 15, CHAARTED and STAMPEDE are three of the most recent academic clinical studies that have intended to elucidate the role of chemotherapy in the scenario of hormone sensitivity in the advanced setting. Although GETUG-AFU 15 did not manage to show benefits in OS, the results from CHAARTED and STAMPEDE studies have unlinked the docetaxel use from the castrate-resistance setting exclusively showing a huge benefit in OS with docetaxel that was never seen before. The CHAARTED study had some controversial aspects, such as the choice of the criteria for high and low-volume metastatic disease, the inclusion of both types of patients in the study, or the arbitrary proportion of each type of patients included in the study. However, the magnitude of the benefit observed in the CHAARTED study cannot be ignored. This controversy has been somehow resolved after the results of the STAMPEDE study. STAMPEDE is the largest study carried out to date on prostate cancer, with over 6000 patients included to date, and it expands the inclusion criteria to high-risk disease. The survival benefit obtained from the addition of docetaxel to ADT is also unprecedented, mainly in the metastatic setting. In both studies, six cycles of docetaxel were well tolerated. Severe adverse events occurred in a few number of patients, and almost all patients received all six cycles so that the benefit obtained exceeded the potential toxicity of this approach.

Despite the fact that we still do not know the long-term results for the low-volume CHAARTED subgroup and the nonsignificant results of GETUG-AFU 15, the impressive results of CHAARTED and STAMPEDE confirm a current change of paradigm and constitute a new standard. Moreover, the systematic analysis of these three studies clearly shows consistent data regarding the use of docetaxel in the hormone-sensitive and metastatic setting although the median OS was still not been achieved in the low-volume subgroup in the CHAARTED study. Besides, European Society for Medical Oncology (ESMO) guidelines [Parker et al. 2015] and European Association of Urology (EAU) guidelines [Mottet et al. 2016] recommend the use of ADT plus docetaxel as first-line treatment of metastatic, hormone-naïve disease in male patients fit enough to receive chemotherapy (Level of evidence: 1, A). For all of these reasons, our patients with a recent diagnosis of metastatic disease should be provided with six cycles of docetaxel in combination with their hormonal therapy in order to improve their chance of survival.

A more difficult question to address is how to determine the mechanism that produces this benefit. Some of the answers will be obtained with clinical studies with innovative design, such as the STAMPEDE study, which will provide future answers to advance in our knowledge and thus, in the treatment of this disease.