New Italian paper below [1]
"Introduction: Recently, there has been a paradigm shift in the treatment of advanced prostate cancer (PCa) because the approval of a number of new agents has significantly improved overall survival. However, as PCa is a heterogeneous disease that may be more or less aggressive and patients may be more or less responsive to treatment, it is often debated whether or not it is acceptable to avoid active therapies. Areas covered: This review discusses different settings of advanced PCa. Expert opinion: In metastatic castration-resistant PCa, it is unethical not to use active treatments but the use of both androgen receptor targeting agents (ARTA) in sequence should be avoided in most patients and the use of the available agents for fourth-line treatment or beyond should only be considered for highly selected patients. In metastatic hormone-sensitive PCa, patients with de novo disease should receive one additional agent in combination with androgen deprivation therapy (ADT), whereas patients in relapse should be managed with ADT alone. In non-metastatic castration-resistant prostate cancer (PCa), all patients with a PSA doubling time of ≤6 months should receive one ARTA, whereas the others might wait until there is an acceleration in the kinetics of their PSA levels."
-Patrick
[1] pubmed.ncbi.nlm.nih.gov/332...
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Extract:
"2. mHSPCa
A number of systemic agents are currently available for the treatment of mHSPCa [19], and the results of two [4, 5] out of three randomised controlled trials (RCTs) [4, 5, 6] have shown that the addition of docetaxel to ADT significantly improved OS in men with mHSPCa. Meta-analyses of these studies have shown that this treatment leads to a 9% absolute improvement in 4-year survival (95% CI 5-14%) [20, 21]. Similarly, two phase III RCTs have shown that adding abiraterone to ADT also significantly improves OS in men with mHSPCa [7, 8], and meta-analysis of these studies have found that the absolute improvement in 3-year survival is 14% [22]. Furthermore, two more recent phase III RCTs have shown that adding enzalutamide [9] or apalutamide [14] to ADT improves OS in comparison with ADT alone.
However, the lack of head-to-head comparisons of docetaxel and ARTAs in this setting raises questions as to how to identify the patients with a better prognosis who can avoid treatment intensification, and whether chemotherapy or ARTAs should be added to ADT for those who are likely to have a poorer outcome [23]. The answers to such questions need to take into account trial endpoints, disease and patient characteristics, and drug safety profiles.
2.1 Survival benefit in published trials (Table 1)
The results of all of the trials except GETUG-AFU 15 [6] show a meaningful improvement in median OS and a similar reduction in risk. An indirect comparison of abiraterone-ADT and docetaxel-ADT demonstrated no statistically significant difference in OS (HR 0.84; 95%CI 0.67-1.06) [24], and comparison of the abiraterone- ADT and docetaxel-ADT arms of the STAMPEDE trial also showed no difference in OS (HR 1.16; 95%CI 0.82- 1.65), although abiraterone-ADT was better in terms of failure-free survival (FFS: HR 0.51; 95%CI 0.39-0.67) and progression-free survival (PFS: HR 0.65; 95%CI 0.48-0.88) [25]. Furthermore, the results of a recent network meta-analysis that indirectly compared the efficacy of ARTAs and docetaxel in patients with mHSPCa showed no difference in terms of OS (HR 0.89; 95%CI 0.76-1.05) [26].
This evidence of improved life expectancy does not support avoiding the addition of docetaxel or ARTAs to
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ADT in mHSPCa patients.
2.2 Disease-related factors for decision making
Two main factors should be considered when defining the risk/benefit ratio of adding docetaxel or ARTAs to ADT in the treatment of mHSPCa: disease volume/risk, and the timing of the onset of metastases.
It seems that the benefit of adding docetaxel/ARTAs to ADT is not the same in all mHSPCa patients. Previous studies have identified a high metastatic burden and de novo metastatic disease as poor prognostic factors associated with shorter survival [27, 28]. The CHAARTED trial first introduced high- volume disease (the presence of visceral metastases or ≥4 bone lesions with at least one beyond the spine
confirmed that docetaxel leads to a survival advantage in men with high-volume disease (HR 0.63; 95%CI 0.50-0.79; p<0.001) and de novo metastatic disease (HR 0.63, 95%CI; 0.49-0.81; p<0.001), but not those with high-volume disease relapsing after local radical treatment (HR 0.72, 95%CI 0.36-0.46; p=0.37). There was also no reduction in the risk of death in the case of patients with low-volume disease as a whole (HR 1.04, 95%CI; 0.70-1.56) regardless of whether they had de novo metastatic disease (HR 0.86, 95%CI 0.52- 1.42; p=0.55) or relapsed metastatic disease (HR 1.25, 95%CI; 0.60-2.60; p=0.55) [29].
Given the uncertain benefit of upfront docetaxel in patients with low-volume mHSPCa observed in the CHAARTED trial, the GETUG AFU 15 [30] and STAMPEDE trials [31] have been assessed on the basis of patient outcomes by disease volume. A meta-analysis of aggregate data retrieved from the CHAARTED and GETUG AFU 15 trials concerning the use of of early docetaxel in mHSPCa patients by disease volume and the timing of the occurrence of metastatic disease (de novo or relapsed) [32] has shown that docetaxel significantly improved OS in the high-volume subgroup (HR 0.68, 95%CI 0.56-0.82; p <0.001), but not in the low-volume subgroup (HR 1.03, 95%CI 0.77-1.38; p=0.8). Moreover, docetaxel significantly improved OS in patients with high-volume disease and de novo metastatic disease (HR 0.67, 95%CI 0.55-0.83), but not in those with low-volume disease regardless of whether their metastatic disease was de novo (HR 1, 95%CI 0.70-1.44) or had relapsed after local treatment (HR 1.12, 95%CI 0.66 -1.90).
and pelvis) as a stratification factor for randomisation
[4], and the updated results of the CHAARTED trial
However, the updated analysis of the docetaxel arm of the STAMPEDE trial did not find any evidence of an
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interaction between the low- and high-volume subgroups [31], although a pooled analysis of the OS HRs of the CHAARTED, GETUG-AFU-15 and STAMPEDE trials has shown that the benefit of adding docetaxel to ADT is uncertain in low-volume patients with mHSPCa (HR 0.91, 95%CI 0.73-1.13; p=0.41)[33].
These conflicting results are probably due to the heterogeneity of the populations enrolled in the trials in terms of the timing of metastases (94% of the patients in the STAMPEDE trial had de novo metastases against 75% in the CHAARTED and GETUG AFU 15 trials), the length of the follow-up, and the availability of life-prolonging agents after treatment failure (given the different years in which the studies were conducted). Nevertheless, on the basis of the findings, it is possible that de novo high-volume metastatic disease is more aggressive and more likely to benefit from treatment intensification by combining ADT and docetaxel, whereas the course of low-volume disease should be indolent and lead to better outcomes regardless of the timing of the onset of metastases, in which case it may be reasonable to avoid chemotherapy and propose docetaxel at the time of castration resistance.
A number of the clinical features of mHSPCa have been evaluated in an attempt to identify subgroups of patients who may benefit more from treatment intensification. The patients in the GETUG AFU 15 trial were stratified into three risk groups (good, intermediate and poor) on the basis of the Glass prognostic model, which includes the sites of bone lesions, Gleason score, PSA levels, and performance status [34], but the effect of docetaxel was not different in the three groups. A post hoc analysis of the GETUG AFU 15 trial has shown that the level of alkaline phosphatase (ALP), Gleason score, and the presence of symptomatic disease are strongly associated with survival [35] but, although the prognostic value of ALP was greater than that of the Glass prognostic model (C-index 0.59, 95% CI 0.52-0.66), it is not useful for discriminating patients with a better prognosis who can avoid treatment intensification with docetaxel.
The LATITUDE trial enrolled only de novo mHSPCa patients with “high-risk” disease, which was defined as the presence of at least two of visceral metastases, ≥3 bone lesions, a Gleason score of ≥8 [8].
The abiraterone arm of the STAMPEDE trial enrolled only 4% of relapsing mHSPCa patients [7]. A recent analysis has shown that the addition of abiraterone to ADT improved OS in mHSPCa irrespective of risk stratification [36] but, as the benefit of adding abiraterone to ADT in patients with relapsed metastatic HSPCa is uncertain, it may be possible to to avoid abiraterone in such patients.
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Disease volume was one of the stratification criteria of the ENZAMET trial, which assessed the efficacy of adding enzalutamide to ADT [9]. Given the results of the CHAARTED trial, the previous use of docetaxel was allowed. Subgroup analysis showed that the beneficial effect of enzalutamide on OS was less in patients with high-volume disease (HR 0.80, 95%CI 0.59-1.07) than in those with low-volume disease (HR 0.43, 95%CI 0.26-0.72). However, the trial was not powered to detect an OS advantage in these subgroups, and the results in the patients with high-volume disease may have been negatively influenced by the administration of docetaxel in this setting (HR 0.90, 95%CI 0.62–1.31). Likewise, the TITAN trial assessed the efficacy of apalutamide in mHSPCa patients stratified by the previous use of docetaxel using a pre- specified analysis of data from patients with low- or high-volume disease [11]. The results of this trial confirmed that the use of apalutamide led to less benefit in terms of OS in the patients previously treated with docetaxel (HR 0.47, 95%CI 0.22–1.01), and no interaction was observed between the low- and high- volume subgroups.
Neither ENZAMET nor TITAN provide any evidence suggesting the possibility of avoiding the use of enzalutamide or apalutamide in some mHSPCa patients on the basis of disease volume. However, no data supported the use of docetaxel and one ARTA and this strategy should not be recommended in everyday clinical practice outside a clinical trial. In particular, on subgroup analysis on ENZAMET there was no additional benefit of giving enzalutamide in patients who had received docetaxel in the hormone-sensitive setting [9].
Further debate concerning mHSPCa treatment strategies has recently been prompted by studies assessing the role of radical radiotherapy. In the STAMPEDE trial, the combination of radiotherapy of the primary tumour and standard of care (SOC) improved FFS (HR 0.76, 95%CI 0.68-0.84; p<0·0001) but not OS (HR 0.92, 95%CI 0.80-1.06; p=0.266) in an unselected mHSPCa population [37]. However, a pre-specified subgroup analysis based on metastatic burden at the time of presentation showed that the addition of radiotherapy significantly improved OS in the patients with a low metastatic burden (HR 0.68, 95%CI 0.52- 0.90), but not in those with a high metastatic burden (HR 1.07, 95%CI 0.90-1.28; p=0·420). Furthermore, the HORRAD trial has confirmed that radiotherapy of the primary tumour plus ADT did not significantly modify OS in comparison with ADT alone (HR 0.90, 95%CI 0.70- 1.14; p=0.4) [38].
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A meta-analysis of these trials has shown that the combination of radiotherapy and SOC improves OS in mHSPCa patients with low-volume disease (HR 0.73, 95%CI 0.58-0.92; p=0.0071) but not in those with high- volume disease (HR 1.07, 95%CI 0.92-1.26; p=0.37) [39], thus supporting the avoidance of local tumour radiotherapy in the latter.
The results of the ongoing randomised phase III PEACE-1 trial (NCT01957436) are awaited to address the question as to whether the addition of abiraterone to radiotherapy and SOC leads to any further benefit. Emerging data concerning metastasis-directed therapy (MDT) in patients with oligometastatic disease (defined as the presence of ≤3 metastases in relapsing or de novo mHSPCa patients) will open up new therapeutic scenarios. The small phase II STOMP trial showed that MDT prolonged median ADT-free survival in comparison with surveillance in patients with oligometastatic mHSPCa (HR 0.60, 80%CI 0.40- 0.90; p=0.37) [40], and this finding has recently been confirmed by the randomised phase II ORIOLE trial [41] in which an MDT-based approach significantly improved median 6-month progression in comparison with surveillance (HR 0.30, 95%CI 0.11-0.81; p = 0.002). Although the small sample sizes, the use of conventional imaging to define oligometastatic patterns, and the choice of surveillance instead of ADT limit the application of MDT in everyday clinical practice, these randomised clinical trials suggest that MDT may delay the use of systemic treatments in this subset of patients.
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Updates to de novo metastatic prostate cancer treatment 
Metformin: Preliminary Results of Trial in Advanced Prostate Cancer (MANSMED)
