Keywords

Introduction

Prostate cancer is the most reported male cancer as well as the second leading cause of cancer-related deaths in Western men, excluding non-melanoma skin diseases (Heidenreich et al. 2014).

Even nowadays, about 10–15% of all men with newly diagnosed prostate cancer harbor systemic metastases with or without symptoms. Metastatic hormone-naive prostate cancer (mhPCA) might be part of a de novo diagnosis of men with newly diagnosed PCA or as progression following local therapies for initially organ confined or locally advanced prostate cancer (Heidenreich et al. 2014). Androgen deprivation therapy by subcapsular orchiectomy has been introduced more than 70 years ago, but median survival time of around 42 months has not changed significantly despite the development of new formulations of testosterone-lowering agents such as LHRH analogues and LHRH antagonists (Hussain et al. 2006). In the STAMPEDE trial, 917 men with mPCA and a median serum PSA concentration of 112 ng/ml were recruited in the control arm and received androgen deprivation therapy (James et al. 2015). After a median follow-up of 20 months, the median failure-free survival was 11 months, and the median overall survival was 42 months with 2-year survival rate of 72%. In multivariate analysis, presence of bone metastases independent on visceral metastases, high Gleason sum score, poor performance status, and younger age strongly correlated with overall survival. In men with high-volume disease median overall survival might be even reduced to 32–35 months (Sweeney et al. 2015; Fizazi et al. 2017).

Continuous ADT by means of orchiectomy, GnRH analogues or antagonists represented the treatment of choice for the last decades. Continuous ADT has been shown to be associated with a longer median overall survival of 5.8 compared to 5.1 years in the intermittent arm of the SWOG 9346 trial (Hussain et al. 2006). The SWOG trial did demonstrate that the PSA nadir at 7 months following initiation of ADT has a major prognostic impact with a median overall survival of 78 months and 17 months if a PSA ≤0.2 ng/ml and a PSA > 4.0 ng/ml were achieved (Fizazi et al. 2017). Therefore, the PSA nadir might serve as an indicator to discuss intermittent ADT in men with good response characteristics as 94% of panelists of the APCCC would do (Gillessen et al. 2015).

As indicated in the STAMPEDE trial, the group of PCA patients with systemic metastases represents a very heterogeneous cohort of men with significantly different survival times depending on the location of metastases, the extent of metastases, the serum concentrations of alkaline phosphatase and PSA as well as the performance status of the patient. Gravis et al. (2015) evaluated the impact of age, performance status, Gleason score, hemoglobin level, PSA, alkaline phosphatase, LDH, metastatic localization, body mass index, and pain on oncological outcome. Visceral metastases, bone metastases, PS (0 vs. 1–2), Hb, ALP, LDH, PSA (≤65 vs. >65 ng/ml), metastases (at diagnosis vs. onset after local treatment failure), and pain intensity (≤16.7 vs. 16.7 or continuous) were significant univariate predictors of OS (p < 0.05). Statistical analysis identified alkaline phosphatase as the strongest predictor of overall survival with a median overall survival of 69.1 months and 33.6 months for patients with normal and with abnormal serum concentrations of alkaline phosphatase, respectively.

Recently, a number of prospective randomized clinical phase-III trials combining ADT with either docetaxel or abiraterone have challenged the traditional therapeutic approach. In addition, few retrospective studies have evaluated the role of local therapy of the primary in order to improving the therapeutic outcome of men with mhPCA.

It is the purpose of this chapter to critically review the current treatment options in patients with mhPCA.

Local Treatment of the Primary

The role of treating the primary tumor in the clinical scenario of metastatic disease is usually ignored in the decision-making process concerning the most appropriate therapy due to the common believe that the biology of the disease is attributed to the metastatic spread and that it cannot be positively influenced by local treatment of the prostate. Quite recently, however, it could be demonstrated that lethal PCA clones persist intraprostatically despite extensive pretreatment with ADT and docetaxel-based chemotherapy (Tzelepi et al. 2011). Furthermore, preclinical studies demonstrated that prostatectomy results in a significant reduction of newly developed metastases in animals subjected to prostatectomy as compared to ADT alone (Cifuentes et al. 2015). A few retrospective and case-control studies demonstrated the feasibility of cytoreductive radical prostatectomy (cRP) and demonstrated a benefit of cRP in terms of time to development of castration-resistant PCA, overall survival, and frequency of locally progressing PCA with lower and upper urinary tract obstruction (Heidenreich et al. 2015; Culp et al. 2014; Sooriakumaran et al. 2015; Gratzke et al. 2014; Fossati et al. 2015; Steuber et al. 2017; Leyh-Bannurah et al. 2017).

There are only very few retrospective studies reporting on the survival outcome following cRP which might serve as hypothesis-generating studies (Heidenreich et al. 2015; Culp et al. 2014; Sooriakumaran et al. 2015; Gratzke et al. 2014; Fossati et al. 2015; Steuber et al. 2017; Leyh-Bannurah et al. 2017). The Cologne study group reported a median CSS and clinical PFS of 47 months and 38.6 months, respectively, after cRP as compared to 40 months and 26.5 months, respectively, in men with ADT alone (Heidenreich et al. 2015). In their retrospective study on a cohort 8185 patients with mPCA, Culp et al. (2014) demonstrated that the 5-yr OS and predicted DSS were each significantly higher in patients undergoing cRP (67.4% and 75.8%, respectively) or brachytherapy (52.6% and 61.3%, respectively) compared with antihormonal therapy alone (22.5% and 48.7%, respectively) (p < 0.001). Sooriakumaran et al. (2015) report on a 2-year survival rate of 89% in a retrospective cohort of 106 patients. Gratzke et al. (2014) retrospectively studied 1538 patients from the Munich Cancer Registry with few bone metastases, of which 74 had cRP and 1464 had no surgery. Those who had surgery showed a 55% survival in contrast to 21% of those who had no surgery. In another retrospective analysis, 8197 mPCA patients were identified from the SEER database 2004–2011 in order to explore the potential benefit of local therapy as compared to nonlocal therapy (Fossati et al. 2015). The authors demonstrated a significant CSS benefit for local therapy (p < 0.0001), especially in patients with a cancer-specific mortality risk <40%. In the most recently published study, Steuber et al. (2017) analyzed the outcome of 43 patients who underwent cRP with 40 patients who underwent nonsurgical therapy only. Although the authors could not identify a survival benefit, they identified a significant benefit for cRP in terms of the prevention of local complications (7% vs. 35%, p < 0.01) despite a median follow-up of only 32.7 months. In another retrospective of 13.692 mPCA patients of whom 474 received local therapy, Leyh-Bannurah et al. (2017) observed a significantly improved cancer-specific survival rate following cRP especially for patients with M1a disease.

Recently, Heidenreich et al. (2018) reported on oncological and functional outcome of the largest series of 121 well-selected men with hormone-naive mPCA who were treated with systemic therapy and cRP with the rationale to improve oncological outcome and to prevent local complications from a progressing primary. Both, the mean OS time and the mean clinical relapse-free survival were high with 86.5 months and 72.3 months, respectively (Figs. 1 and 2). Additionally, they showed a 1-, 3-, and 5-year survival rate of 98%, 87.8%, and 79%, respectively. These data underline the potential role of cRP in the individual management of men with newly diagnosed mPCA if included in clinical protocols.

Fig. 1
figure 1

Overall survival of the cohort of 113 patients. CE cumulative number of events, NR numbers at risk

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Fig. 2
figure 2

Clinical relapse-free survival. CE cumulative number of events, NR numbers at risk

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Although the group was not able to identify preoperative parameters associated with OS, they identified preoperative PSA and the extent of metastatic disease as indicators for an improved biochemical PFS. Patients who achieved a PSA nadir <1.0 ng/ml following neoadjuvant ADT, patients with a PSA below the median preoperative PSA of 8 ng/ml, and men with low-volume metastatic disease exhibited a significantly better outcome. These patients might be the most appropriate candidates for CRP as the prognosis seems to be excellent.

With regard to surgery-associated complications, perioperative and 90-day mortality rate were 0%. These data underline that cRP represents a technically feasible and safe procedure if performed by experienced surgeons. In addition, we could demonstrate that patients with low-volume metastatic disease, a preoperative PSA < 4 ng/ml, and neoadjuvant ADT experienced significantly less serious complications.

Functional outcome in terms of urinary continence also was in line with data of RP for locally advanced PCA: 68% and 18% of patients achieved complete or minimal incontinence. Following RP for clinical T3 disease, continence rates vary between 70% and 80% considering patients with total continence or the use of one safety pad.

When considering surgery-related complications of cRP, one also has to consider the local and systemic complications if ADT is performed as monotherapy. In their two retrospective studies, local complications were observed in 29% of patients of the ADT group after a mean follow-up of 44 months, whereas none of the patients in the cRP group experienced such complications (Heidenreich et al. 2015, 2018). Similarly, Poelaert et al. (2017) demonstrated significant differences in local complications between cRP and ADT alone. At 3 months of follow-up, five (29.4%) patients undergoing cRP reported stress urinary incontinence without any further local symptoms, whereas 6.8%, 37.9%, and 6.8% of patients suffered urge incontinence, obstructive voiding, and ureteric obstruction following ADT alone.

In addition, the study of Rusthoven et al. (2016) underlines the importance of effective local therapy of the primary. The authors demonstrated a superior median (55 vs. 37 months) and 5-year OS (49% vs. 33%) with prostate RT plus ADT compared with ADT alone (p < 0.001). In a similar approach, Joensuu et al. (Heidenreich et al. 2018) demonstrated a 5-year overall survival of 81.3% and a median OS time of 8.35 years in a super-selected group of 46 men with mPCA who underwent ADT plus IMRT.

Despite the favorable results of local treatment in mPCA, we have to be aware of the limitations concerning the current data. All studies are retrospective in nature, and only selected patients have been treated so that cytoreductive local therapy in mPCA is still an individual and experimental therapy and it does represent the standard of care. Currently a number of prospective randomized trials of ADT ± surgery or ADT ± radiotherapy are ongoing, and we have to await the final results.

Systemic Treatment in mPCA

ADT Plus Docetaxel-Based Chemotherapy

The CHAARTED trial was the first prospective randomized clinical phase-III trial comparing the therapeutic efficacy of androgen deprivation therapy versus the combination of ADT plus docetaxel (Sweeney et al. 2015). 790 patients were randomized to receiving either continuous ADT with LHRH analogues or surgical castration (n = 393) or a combination of continuous ADT with six cycles of docetaxel at a dose of 75 mg/m2 delivered at 3-week intervals (n = 397). A time interval of up to 120 days was allowed between initiation of ADT and systemic chemotherapy. The primary endpoint of the trial was improvement of overall survival. Secondary endpoints were progression-free survival, PSA response, etc.

Patients were stratified according to age, extent of disease (low risk vs. high risk), ECOG performance status, medical prevention of skeletal-related events, and previous adjuvant ADT. High-risk disease was defined by the presence of visceral metastases or the presence of at least four skeletal metastases with one being located outside the axial skeleton.

After a median follow-up of 28.9 months, a significant survival benefit of 13.6 months (57.6 months vs. 44 months) with a hazard ratio of 0.61 (95% CI, 0.47–0.80, p < 0.001) was observed resulting in a 39% relative risk reduction of prostate cancer death. The only stratification with significant impact on survival was the presence of low-risk versus high-risk disease. Patients in the high-risk disease group achieved a survival benefit of 17 months (49.2 vs. 32.2 months) with the combination of ADT plus docetaxel resulting in a 40% relative risk reduction of death (HR = 0.60, 95% CI 0.45–0.91, p < 0.001). No survival benefit was observed in the low-risk PCA cohort where the median overall survival has not been reached in both arms (HR = 0.60, 95% CI 0.32–1.13, p = 0.11). Even at long-term follow-up, no survival benefit was observed for the low-risk group, whereas the survival advantage was validated for the high-risk group. Forest plot analysis did demonstrate a survival benefit for all subgroups even for the groups of elderly men, patients with poor performance status, and visceral metastases with or without bone metastases.

Quite recently, the authors performed a landmark survival analysis 7 months after initiation of therapy using the SWOG9346 PSA cut points of ≤0.2 ng/ml, >0.2–4.0 ng/ml, and > 4.0 ng/ml (Harshman et al. 2018). The median follow-up which started after 7 months of ADT was 23.1 months. The median overall survival was significantly longer in the total cohort of patients when comparing a PSA serum concentration ≤ 0.2 ng/ml versus >4.0 ng/ml (Table 1). Patients with visceral metastases had a higher likelihood of not achieving a PSA ≤ 0.2 ng/ml, and in fact the percentage of patients with visceral metastases and a 7-month PSA > 4.0 ng/ml was 20.9% as compared to only 12% in the group of men with a 7-month PSA ≤0.2 ng/ml (Fig. 3).

Table 1 Median overall survival dependent on PSA nadir after 7 months of ADT therapy
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Fig. 3
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Overall survival depending on a PSA serum level < 0.1 ng/ml (red) or > 0.1 ng/ml (blue) 6 weeks postoperatively, p = 0.0003. CE cumulative number of events, NR numbers at risk

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The STAMPEDE trial is another adaptive, multiarm, multistage, randomized controlled trial in which the addition of docetaxel, zoledronic acid, or both to first-line continuous ADT was evaluated (James et al. 2016). In this trial, a total of 1184, 993, 992, and 993 men received standard hormonal therapy, ADT plus ZA, ADT plus docetaxel, or ADT plus ZA and docetaxel, respectively, with the primary endpoint to improving overall survival. It has to be noted that a total of 2962 patients were included in the trial but that 1145 (42.5%) patients did not exhibit metastases, whereas 1817 (56.5%) men were newly diagnosed with metastatic disease.

After a median follow-up of 43 months, the median overall survival time in men with mPCA was 45 months in the ADT-alone group with a 5-year survival rate of 39%. There was no benefit in the median overall survival time in the ADT plus ZA group with 46 months and a 5-year survival rate of 43% (HR = 0.93, 95% CI 0.77–1.11, p = 0.416). A significant survival benefit, however, could be observed for the ADT plus docetaxel arm with a median overall survival time of 60 months and a 24% relative risk reduction of death (HR = 0.76, 95% CI 0.62–0.92, p = 0.005). The 5-year survival rate was 50%. A similar survival benefit was observed for the combination of ADT plus ZA and docetaxel with a median survival time of 55 months and a 21% relative risk reduction of death (HR = 0.79, 95% CI 0.66–0.96, p = 0.015). Comparing the groups of ADT plus docetaxel and ADT and ZA plus docetaxel, no survival benefit was observed for the addition of ZA (HR 1.06, 95% CI 0.86–1.30, p = 0.592). A similar benefit was observed for ADT plus docetaxel and ADT and ZA plus docetaxel concerning prostate cancer-specific survival.

In addition, the potentially positive impact of ZA on the development of skeletal-related events (SRE) was evaluated. 328/1184 (xx%) patients randomized to ADT alone developed SREs. The time to first SRE was improved with ADT plus docetaxel (HR 0.60, 95% CI 0.48–0.74, p = 0.0000127) and with ADT and ZA plus docetaxel (HR 0.55, 95% CI 0.44–0.69, p = 0.277x10−7), but it was not improved with ADT plus ZA (HR 0.89, 95% CI 0.73–1.07, p = 0.221). Concentrating on the patients with skeletal metastases, there was also no benefit of ADT plus ZA on the time to first SRE and frequency of SRE (HR 0.94, 95% CI 0.76–1.16; p = 0.564). Taking into consideration the whole cohort of patients, the median to the development of SREs was 61.4 months, 68.0 months, and 68.3 months, for ADT alone, ADT plus docetaxel (p = 0.177 < 10−4), and ADT and ZA plus docetaxel (p = 0.249x10−5), respectively.

Finally, the GETUG-15 trial (Gravis et al. 2013) did not identify a survival benefit between the ADT alone and the ADT plus docetaxel group after a median follow-up of 83.3 months with a median survival of 48.6 and 62.1 months (HR 0.88, 95% CI 0.68–1–14, p = 0.3). Subgroup analysis trended to be in favor of a survival advantage for the combination therapy in men with high-volume disease. However, the subgroups were too small for a conclusive data analysis.

Based on these data, all international guidelines recommend the combination of chemo-hormonal therapy for men with high-volume disease, whereas ADT alone should be the preferred treatment in men with low-volume, metastatic hormone-naive prostate cancer (Morris et al. 2018; Gillessen et al. 2018). The addition of ZA is not recommended in addition to ADT alone or to combination of ADT plus docetaxel.

ADT Plus Abiraterone and prednisone

Following the life-prolonging impact of AA/P in patients with metastatic castration-resistant PCA prior to and following docetaxel chemotherapy, two trials evaluated the therapeutic efficacy of AA/P plus ADT versus ADT alone in men with newly diagnosed, hormone-naive mPCA (Fizazi et al. 2017; James et al. 2017).

The LATITUDE trial recruited a total of 1199 patients with mhPCA who exhibited at least two of the three high-risk criteria which were a Gleason score ≥ 8, ≥3 lesions on bone scan, and visceral metastases (Fizazi et al. 2017). Patients were randomized in a 1:1 fashion so that 597 men were randomized in the combination arm (abiraterone acetate at a dose of 1000 mg/day, prednisone 2 × 5 mg/day, and continuous LHRH analogues) and 602 men were randomized in the standard arm. The co-primary endpoints were overall survival and progression-free survival. The secondary endpoints were time to pain progression, time to PSA progression, time to symptomatic SREs, and time to chemotherapy and safety.

After a median follow-up of 30.4 months, there was a statistically survival benefit in the ADT plus AA/P group in which the median overall survival was not reached versus 34.7 months in the ADT alone (HR 0.62, 95% CI 0.51–0.76, p < 0.0001). Also, the second primary endpoint was met with a statistically significant benefit of 18.2 (33.0 vs. 14.8 months) concerning radiographic progression-free survival (HR 0.47, 95% CI 0.39–0.55, p < 0.0001). In addition, all secondary endpoints were met and demonstrated a statistically significant benefit for the ADT plus AA/P group (Table 2).

Table 2 Secondary endpoints in LATITUDE for the treatment and the placebo group
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Treatment-associated side effects did not occur at higher frequency or severity in the treatment arm as compared to the placebo arm. The profile of side effects did resemble the well-known scenario of AA/P in the COUGAR-301 and COUGAR-302 trials.

With regard to the treatment sequence at time of progression, it became evident that only 53% of the patients in the AA/P arm were thought to be fit enough to receiving a second-line therapy as compared to 78% in the placebo arm. Furthermore, only 38% as compared to 46% of patients in the AA/P and the placebo arm received some type of systemic chemotherapy, respectively.

In a similar approach, 1917 patients with hormone-naive PCA were randomized in a 1:1 fashion to receive AA/P plus ADT versus ADT alone in the STAMPEDE trial (James et al. 2017). Different to the LATITUDE trial, no regulation with regard to the inclusion of only high-risk patients was given. Patients with newly diagnosed and node-negative PCA and newly diagnosed node-positive and newly diagnosed metastatic PCA could be recruited for the trail. A total of 941 patients belonged to the group of newly diagnosed metastatic, hormone-sensitive PCA of whom 476 and 465 patients were randomized to receiving ADT and ADT plus AA/P, respectively. Those patients form the basis of the current chapter.

After a median follow-up of 40 months, a statistically significant survival advantage was observed for the group of patients receiving the combination therapy versus the ADT alone group. 218 versus 150 deaths were observed in the ADT group and the ADT plus AA/P group, respectively, resulting in a 39% relative risk reduction of death (HR 0.61, 95% CI 0.49–0.75). Forest plot analysis reported a statistically significant survival benefit of AA/P plus ADT for all subgroups except for elderly patients ≥70 years. Similar data were achieved with regard to failure-free survival where a 69% relative risk reduction (HR 0.31, 95% CI 0.26–0.37) was observed for the combination group.

In STAMPEDE, a higher frequency of grade 3–5 adverse events was observed in the combination group with 47% as compared to the ADT group with 33%. Especially cardiovascular disorders (10% vs. 4%), hepatic disorders (7% vs. 1%), and respiratory disorders (5% vs. 2%) developed much more often in the combination group. There was, however, no difference with regard to adverse events of grade 5 only (1% in both groups).

With regard to treatment at time of progression, the absolute number of patients receiving life-prolonging agents was higher in the ADT-alone group as compared to the combination group (310 vs. 131 patients).

Based on these two prospective randomized trials, the combination of ADT and AA/P exerts a statistically significant and clinically relevant advantage in terms of overall survival and failure-free survival as compared to ADT alone in men with newly diagnosed metastatic and hormone-naive prostate cancer (Morris et al. 2018; Gillessen et al. 2018; James et al. 2017; Mottet et al. 2017; Rydzewska et al. 2017). The increased frequency of grade 3–5 adverse cardiovascular, hepatic, and respiratory events has to be taken into consideration when counseling patients.

Sequencing Strategies

No data on the best sequencing strategy exist so that no reliable and valid recommendations can be given with regard to best sequence (Morris et al. 2018; Gillessen et al. 2018; James et al. 2017; Mottet et al. 2017; Rydzewska et al. 2017).

Comparing CHAARTED and LATITUDE with regard to their oncological efficacy, various findings need to be taken into consideration. The LATITUE trial only allowed high-risk patients to be recruited so that outcome data of high-risk and high-volume disease (CHAARTED) should only be compared.

The median overall survival in the ADT alone was nearly identical in both high-risk and high-volume groups with 34.7 months and 34.4 months in LATITUDE and CHAARTED, respectively. Radiographic progression-free survival was 14.8 months and 13.0 months for the ADT-alone group in LATITUDE and CHAARTED, respectively, whereas PFS was 33.0 and 27.3 months in the treatment group resulting in a relative risk reduction of 53% and 47% in LATITUDE and CHAARTED, respectively. Concerning overall survival, both trials achieved a similar benefit with a relative risk reduction of death of 38% and 37% in LATITUDE and CHAARTED, respectively.

Concerning the treatment-associated adverse events, one has to consider the significantly increased frequency of cardiovascular, hepatic, and respiratory events in the combination arm as compared to the ADT-alone arm in the LATITUDE trial (22% vs. 7%, respectively). The median treatment duration of 33 months with side effects such as fatigue, cognitive dysfunction, etc. also needs to be taken into account. With regard to ADT and docetaxel, the risk of neutropenia was 32%, 3.1%, and 12% in the GETUG-15, CHAARTED, and STAMPEDE trial. The risk of neutropenic fever was 7%, 3.8%, and 15% in GETUG-15, CHAARTED, and STAMPEDE. Considering these adverse events, it needs to be taken into consideration that the median treatment duration of docetaxel was 4.5 months and that basically all patients recovered rapidly after discontinuation of chemotherapy. Comparing both treatment options, one needs to take into consideration the pre-existing chronic comorbidities which might interfere with abiraterone or docetaxel.

With regard to the sequence, one also has to consider the different rates of follow-up therapies in men who have received AA/P or docetaxel. Whereas 88% and 83% of patients in the ADT-alone group and in the docetaxel group received a life-prolonging second-line therapy, only 53% as compared to 78% of patients in the ADT alone and in the AA/P group were thought to be fit enough to receiving a follow-up treatment with life-prolonging agents. One might consider first-line chemotherapy especially in elderly patients with relevant comorbidities who might not be fit enough to receiving chemotherapy after long-term ADT therapy.