This follows on from my response to the YONSA post.
From a recent paper [1]:
"Despite the fact that free testosterone (FT) is the biologically active form, it is common practice that androgen suppression is monitored via total testosterone levels only."
"A total of 34 patients with continuous measurements of FT levels and mCRPC status underwent therapy with docetaxel, abiraterone acetate, enzalutamide, cabozantinib, carboplatin or cabazitaxel."
"Despite the fact that all patients were undergoing androgen deprivation, the mean serum FT levels for each patient varied; the mean FT concentration in the cohort was 0.328 pg/ml, ranging from 0.01-9.1 pg/ml."
"A notable difference with regard to CSS {cancer-specific survival} was observed for patients with regard to serum FT concentration; CSS was significantly longer for patients with a serum FT level below the cutoff level (43.6 vs. 17.3 months, respectively"
{cutoff point = 0.5 pg/ml}
-Patrick
[1] ncbi.nlm.nih.gov/pubmed/281...
FULL Text: ncbi.nlm.nih.gov/pmc/articl...
Discussion {ONLY} - worth reading!
When prostate cancer progresses apparently independent of conventional hormonal manipulation, the question arises as to whether a conventional ADT regimen should be continued during second-line ADT. Abiraterone acetate and enzalutamide exert their effects on intracellular signaling by more substantial and firm effects on androgen biosynthesis and androgen receptor binding than their predecessors: LHRH analogues cause a downregulation of LHRH receptors in the pituitary gland, thereby decreasing the release of gonadotropins and consecutively the production of testosterone; however, this effect on prostate neoplastic cells is confined to the hypothalamic-pituitary-gonadal axis (18). Abiraterone decreases serum testosterone and androgen levels by inhibiting 17α-hydroxylase/C17,20-lyase in steroid biosynthesis, and is not only limited to the testicular Leydig cells, but is also exerting its effect in the adrenal gland and in prostate cancer cells (19). First-generation non-steroidal anti-androgens, including flutamide and bicalutamide, block the androgen receptor, thereby inhibiting intracellular signaling. Enzalutamide has a higher binding affinity to the androgen-receptor, and it not only acts competitively at the receptor level, but also blocks the activation of androgen-responsive genes and inhibits the preceding translocation of the homodimerized receptor-ligand (20). Applying LHRH analogues or non-steroidal anti-androgens while administering abiraterone acetate or enzalutamide may therefore appear redundant when considering modes of action for these substances. The concept of continued conventional ADT and serum testosterone level monitoring with regard to clinical parameters and overall survival (OS), originates from a notable study by Perachino et al, showing a clear association between OS and serum testosterone levels measured 6 months after initiation of ADT (21). The study was based on previous results of a study by Morote et al, in which it was deduced that from a cohort of 73 patients, ~25% of all men being treated with LHRH-depot injection exhibited testosterone levels higher than the formerly recommended serum level of 0.5 ng/ml. The study found a direct correlation between ‘androgen-independent’ (originally used expression) progression and serum testosterone levels. It was also able to show that breakthrough increases of testosterone levels during LHRH agonist therapy exhibited a markedly negative effect on ‘androgen-independent’ progression. The mean survival time, free from ‘androgen-independent’ progression, was 137 months for the subgroup of patients without breakthrough increases of testosterone and it decreased to 88 months for patients with breakthrough increases of >32 ng/dl (22).
The study by Byar was also able to show a contributing effect of insufficient androgen suppression on overall mortality, however, this effect was observed with the administration of diethylstilbestrol (23), and unlike our current study, not with LHRH analogues in conjunction with abiraterone acetate or enzalutamide.
Other retrospective studies evaluating the positive effects of continued ADT therapy in patients with CRPC have also shown survival advantages for patients who sustained LHRH analogue therapy (24,25). These findings clearly emphasize the requirement for laboratory monitoring of ADT therapy, however, the aforementioned studies were undertaken a long time prior to the advent of second-line anti-androgens. Also, the previously mentioned studies by Morote et al (22) and others, used total testosterone, which is easier to measure than FT. In the current study, an emphasis was placed on FT, which is the active fraction responsible for biological activity (11). Notably, there is not yet much data on FT with regard to prostate cancer.
A more recent finding that does potentially support the continuation of LHRH therapy, including serum testosterone measurements on a regular schedule, was derived from the COU-AA-301 study itself (26). Data from the trial, initially comparing the efficacy of abiraterone acetate plus low-dose prednisone versus prednisone only, was subsequently analyzed with regard to androgen dynamics in correlation with serum PSA: In an ultra-sensitive assay, PSA measurements showed a reduction to undetectable levels in 47% of patients in the abiraterone arm, while none of the patients continuing regular androgen deprivation exhibited serum testosterone levels below the detection threshold. The study compared androgen levels with radiographic progression-free survival and time to PSA progression, but found no significant correlation. However, unlike the present study, the measurements were timed exclusively 12 weeks after the initiation of therapy. Additionally, the focus was on total testosterone concentration and not FT levels. Nonetheless, these findings show that inadequate androgen suppression may and does occur in patients with inhibition of the hypothalamic-pituitary-gonadal axis, even when combined with inhibitors of precursor steroid biosynthesis (27). Notably, 13–42% of patients under therapy with LHRH analogues fail to reach serum testosterone levels of <0.5 ng/ml (28). These involuntary elevations of serum testosterone may provide an insight as to what extent circulating androgens play a role in the advanced mCRPC setting when next-generation ADT is in place. The reason for the significant increases of androgen levels under therapy is not fully understood. Certain men may experience a surge in serum testosterone concentration while under long-term therapy with LHRH analogues. This phenomenon was previously described as the ‘acute-on-chronic response’ (29). Also, obese patients tend to have higher testosterone concentration levels under LHRH therapy than men with a normal body mass index (30). Other reasons for insufficient androgen suppression are a faulty preparation of the LHRH depot injection or inadvertent discontinuation of therapy. While FT and total testosterone concentrations can frequently be assessed, the aforementioned reasons for insufficient androgen suppression cannot adequately be identified or monitored. The present study showed a variance in FT serum concentration. However, it did not provide a clear explanation for these surges in FT levels. One possible incentive for the continuation of conventional ADT may lay in the assumption of a broader mode of therapy in the castration-resistant state. The mechanisms that lead to the castration-resistant state are numerous and have been subjected to extensive research in the past. Intracellular cell signaling promoting growth and tumor progression may continue by means of ‘bypass’ or ‘outlaw’ pathways, even without the binding of the androgen receptor ligand. One example for these mechanisms is the expression of B-cell lymphoma 2, which is a critical anti-apoptotic protein in CRPC and prostate cancer in general (31). Another example is the Akt signaling cascade (32) or the overexpression of human epidermal growth factor receptor-2/neu tyrosine kinase. The latter is able to boost prostate cancer growth and androgen receptor signaling independently of the androgen ligand binding to the receptor (33). These models for the alternate activation of prostate cancer cells appear to be independent of androgen signaling and do not give a clear justification for the continuation of LHRH therapy in the mCRPC state. Androgen receptor splice variant-7 (AR-V7), presented at the 2014 Genitourinary Cancer Symposium annual meeting, lacks the ligand-binding domain for enzalutamide, but it remains active as a transcription factor. PSA response rates were 0% for abiraterone and enzalutamide in patients with the AR-V7 splice variant, which directly translated into shorter progression-free survival times (34). However, these data do neither support nor negate the beneficial effect of an ongoing conventional ADT while starting with enzalutamide or abiraterone acetate. Free androgen levels appear to significantly affect CSS, as shown in the current study. This indicates that progression in a cohort of patients with mCRPC is not merely driven by escape mechanisms and resistance completely independent of androgen signaling, but is dependent on serum FT levels, even with the combination of conventional ADT and second-generation hormone manipulation. This finding can be explained through clonal heterogeneity or by resistance mechanisms that rely on FT, such as androgen receptor overexpression (35,36). We hypothesize that one possible argument in favor for continuing conventional ADT, while administering enzalutamide or abiraterone acetate, may be an overlap in treatment that could potentially reduce the risk of FT surges due to accidental pauses of treatment. One of the most notable studies with regard to LHRH therapy during second-line hormonal manipulation was conducted by Pinski et al, which showed that LH receptors exist on prostate cancer cells and stimulate cancer growth by increasing intrinsic steroidogenesis (37). This finding would be an argument in favor for the continuation of conventional LHRH analogue therapy. The inhibition of steroid biosynthesis in addition to LHRH analogue therapy is not new; it was used even prior to the advent of abiraterone acetate, when ketoconazole was combined with complete androgen blockade resulting in a markedly lower testosterone concentration when compared to complete androgen blockade alone (38). Probably the most important argument in favor of the continued use of LHRH analogue therapy in the mCRPC state is, however, the lack of clinical studies with regard to survival. The current study, therefore, may represent one of the first pieces of clinical evidence on the topic.
The current study was limited by its retrospective design and the heterogeneity of treatments that, however, reflect the therapeutic reality of patients with mCRPC today.
In conclusion, patients with advanced mCRPC who have progressed under conservative ADT have FT as a significant predictor of CSS, even in the sequence of second-generation ADT (abiraterone acetate or enzalutamide) and chemotherapy. The present findings support the recommendation that LHRH-analogue therapy and measurements of androgen suppression on a regular basis should not be omitted in this setting.
Testosterone “Flare” (Or Testosterone?) Timing to Optimize Salvage Radiation Therapy
Skip the injection, go straight to abiraterone
