Prostate cancer (PCa) is a prevalent male genitourinary malignancy characterized by an insidious onset and indolent progression. The incidence of PCa exhibits substantial geographic heterogeneity, with higher rates observed in developed regions including North America, Australia, and Northern Europe, contrasting with lower rates in developing areas such as Southeast Asia (1). This disparity likely reflects contributions from genetic predisposition, family history, environmental factors, and lifestyle (2, 3). Globally, PCa incidence has risen overall while mortality has declined; notably, incidence displays greater spatial and temporal variation than mortality (4). The reduction in PCa mortality, however, is predominantly evident in economically advanced nations, with the most pronounced decreases occurring in high-income countries. These trends are attributable to the widespread adoption of prostate specific antigen (PSA) screening (impacting incidence) and therapeutic advancements (reducing mortality) (5–7). PCa incidence correlates strongly with age, exhibiting a progressive increase in older populations (8, 9). Prostate cancer demonstrates familial aggregation, genetic susceptibility, diverse histopathological subtypes, and heterogeneous treatment responses. Androgen deprivation therapy (ADT) constitutes the cornerstone of endocrine treatment for PCa and is utilized across cancer stages. Both gonadotropin-releasing hormone (GnRH) agonists and antagonists are established standard agents for ADT, achieving castration-equivalent testosterone suppression, pharmacological castration throughout ADT is generally comparable to surgical castration in efficacy (10). Testosterone plays a critical role in advanced PCa (aPC), traditionally, castration testosterone level is<50ng/dL, but beyond castration, redefining maximal testosterone control in aPC.

Prostate cancer exhibits high androgen dependence, with testosterone driving tumor growth; thus, ADT constitutes the therapeutic cornerstone. No significant intergroup differences existed in age distribution (P = 0.629) or Gleason scores (P = 0.119), castration low, castration and non-castrated, suggesting minimal influence of these factors on testosterone response to ADT. Approximately half of patients were aged >73 years—notably, PCa mortality risk increases from 17% (diagnosis age<70) to 21% (≥70) (12). Age independently predicts inferior survival post-ADT, with significantly better outcomes in patients aged 71–75 versus >75 years (13). Visceral metastasis and tumour load differed significantly between groups (both P<0.05), predominating in the non-castrate cohort (27.78% and 74.07%, respectively). This also implies that visceral metastasis and tumour load seem to have a relatively important effect on the sensitivity of testosterone response with ADT treatment, especially when extra-regional visceral metastasis and high tumour load have occurred. ADT parameters (Testosterone 1 month after ADT, ADT time, ADT continuity and ADT dosage form) also varied substantially (all P<0.01). Intermittent ADT (IADT) prolongs median time to mCRPC versus continuous ADT (CADT) (14). In aPC, IADT can produce oncologic outcomes similar to CADT. In terms of overall survival, the hazard ratios for IADT and CADT were very similar (range: 0.98-1.08) (15). Maintaining serum testosterone<20–30 ng/dL extends ADT response (16).

Tumour progression between different groups, TTP classification and time were significantly different between groups (P<0.001), and significant difference between both groups (P<0.001). Specifically, the castration low T level group had TTP of 24.62 ± 13.62 months and the lowest percentage of TTP<18 months (33.88%), the castration T level group had TTP of 15.65 ± 9.16 months with the second highest percentage of TTP<18 months (64.34%), the non-castrated T level group had TTP of 10.93 ± 7.89 months with the highest percentage of TTP<18 months (83.33%). Lower nadir testosterone correlated with longer TTP. The 18-month threshold reflects typical transition to castration resistance, because PCa is mostly hormone-sensitive at first diagnosis, but tends to progress to castration resistance after 18–36 months of endocrine therapy. ADT is the standard of treatment for patients with aPC. However, the castration serum testosterone threshold, as well as the time to progression to mCRPC in patients with newly diagnosed aPC remain controversial. While<50 ng/dL does not predict ADT efficacy, testosterone ≤25 ng/dL at 1 month optimally predicts prolonged TTP (adjusted HR: 1.46; 95% CI: 1.08–1.96; P = 0.013) ( 17). Paradoxically, lower baseline testosterone (<12 nmol/L) associates with earlier mCRPC development (19.0 vs. 22.4 months; P = 0.031) ( 18). There was a significant difference in survival rates between three groups (P<0.001), and significant difference between both groups (P<0.001). Castration low T level had significantly higher survival rates at both 3 years (median survival rate,80.30%) and 5 years (median survival rate,63.67%), and non-castrated T level had the worst prognosis. However the exact relationship between testosterone levels and the prognosis of PCa remains under-explored. Prognostically, low diagnostic testosterone (2.0–8.0 nmol/L) independently predicts reduced OS (19). Low serum testosterone level (<450ng/dL) in metastatic hormone sensitive prostate cancer (mHSPC) patients with ADT predicted a poor prognosis, and CRPC-free survival and overall survival in the low-testosterone group were significantly shorter than those in the high-testosterone group (P = 0.021 and P<0.001) ( 20). Lower baseline serum testosterone (<250ng/dL) was significantly associated with poorer survival outcomes in patients with first-treatment mHSPC undergoing CADT (21). Minimum testosterone of 20 ng/dL is the most significant critical level for overall survival in PCa with ADT therapy (22, 23). However it has also been suggested that a minimum testosterone value of 30 ng/dL provides the best overall sensitivity and specificity for predicting death. Serum testosterone level<30 ng/dL was associated with a significantly lower risk of death (adjusted HR,0.45;95%CI,0.22-0.94; P = 0.034) ( 24). In this study, it was concluded that in patients with aPC, with ADT testosterone minimum set at 10 ng/dL seems to be more appropriate and the clinical survival benefit is more favourable. In addition, the time to arrival of testosterone nadir tends to be about 1 year or less. The rate of descent to minimum testosterone early in ADT treatment (6 months) was categorised as rapid or slow, with no significant difference in overall survival (22). Thus the key factor in prognosis is not the testosterone rapid decline, but whether the lowest testosterone reaches below the desirable threshold.

Castration low T level (<10ng/dL) was divided into two groups, castration ultra-low (5-10ng/dL) and castration extreme low testosterone level (<5ng/dL). To assess whether maximal testosterone suppression (almost no testosterone) confers incremental benefit, the study inclusion of surgical castration (bilateral orchiectomy) combined with flutamide or bicalutamide in a small sample of data, the default testosterone 0ng/dL, basically no testosterone level, to compare whether there is a difference in progression and survival in PCa. The tumour progression between the different subgroups did not show any significant difference in TTP time between the groups (P = 0.794), nor between the two groups (P>0.05). With improved prognosis in patients with testosterone suppression below 20 ng/dL and even 10 ng/dL, but with ADT minimum testosterone<10ng/dL continued subgroup stratification appeared to make no difference for PCa progression. Testosterone breakthrough, or an elevation of testosterone above the castration threshold from the first month to the sixth month of ADT, is usually associated with inadequate ADT treatment or insensitive ADT treatment. The weighted mean testosterone breakthrough rate was significantly higher for the 20 ng/dL threshold compared with 50 ng/dL (41.3% vs 6.9%, P<0.0001), and clinical factors such as frequency of testosterone monitoring, testosterone test method and route of ADT administration did not significantly affect testosterone breakthrough rate (25). Early standard ADT reduces symptoms of cancer progression in advanced hormone-sensitive prostate cancer and may prolong progression-free survival and overall survival (26, 27).

The results of this study show a difference in survival between the castration extreme low T level (<5ng/dL), castration ultra-low T level (5-10ng/dL) and basically no T level (0ng/dL) groups (P<0.001). Castration extreme low T level and castration ultra-low T level did not differ in 3 and 5-year survival, whereas basically no T level had the worst prognosis compared to the other two groups, with a median 5-year survival was 32.24% and median 3-year survival was 58.62%, which demonstrates that with ADT castration with a minimum testosterone level of less than 5ng/dL has no survival difference over 5-10ng/dL, but surgical castration (complete androgen blockade, testosterone almost 0ng/dL) has the worst prognosis, suggesting that near-complete androgen suppression (0 ng/dL) may not improve outcomes, instead, it leads to a worse prognosis. The low testosterone response often depends not only on the individual sensitivity to androgen deprivation therapy, but also on the synergistic effects of combination therapy. Combination therapy based on ADT possesses efficacy and safety in mHSPC, and combination therapy achieves better survival outcomes than ADT alone (28). Early intensive treatment of mHSPC, especially in patients with high tumour load, is clinically recommended to be suitable for ADT-based chemotherapy triple therapy, which is more beneficial than double therapy for overall survival (29–31). The correlation analysis of testosterone minimum and time to progression showed that there was a weak negative correlation (r=-0.32, P<0.001), no negative correlation between testosterone minimum and OS (r=-0.29, P<0.001). While there was a medium positive correlation between testosterone 1 month after ADT and testosterone minimum (r=0.65, P<0.001), there was a medium positive correlation between TTP and OS (r=0.50, P<0.001). Further demonstrating that low testosterone represents maximal testosterone control, thereby slowing cancer progression. But in the complex environment of the real world, patients with aPC, priority must be given to determining which treatment combinations and sequences of treatment will be of greatest benefit (32). And taking into socio-personal, economic-temporal multiple factors and respecting self-selection.

It has been found that after castration treatment, 5-10% of pre-treatment androgen levels are often still present in prostate tissue, due to the fact that in addition to androgens produced by the testes, residual androgens are secreted by the adrenal glands and other glands. For blocking androgens, treatment with anti-androgen drugs is also required. Competitive inhibition of androgens, which cannot bind to tumour receptors, is known as maximal androgen blockade (MAB). Surgical castration is one of the ancient and traditional methods of MAB, and postoperative androgen levels can be rapidly reduced to the desired goal (ranges from 3 to 12 hours, average 8.6 hours) (33), serum testosterone level was approximately 15 ng/dL (34). The study also additionally included surgical castration (bilateral orchiectomy) combined with flutamide or bicalutamide. Surgical castration was defaulted to 0 ng/dL of testosterone in the study, and testosterone was only considered to be a single source from testes, not including exogenous testosterone replacement and extra-testicular. Testosterone replacement therapy is not routinely administered to all older men with low testosterone levels, but it is recommended that individualised treatment may be considered, when appropriate. For old men with low-risk PCa who have persistently low testosterone level and significant symptoms, risk-benefit analysis (35, 36).

In androgen deprivation therapy, the nadir serum testosterone level and its fluctuation range constitute independent prognostic factors distinct from traditional PSA metrics. Achieving and sustaining deeper, more stable testosterone suppression (recommended testosterone castration level 10 ng/dL) delays cancer progression and extends survival. This contrasts with the conventional view, where androgen deprivation therapy merely aims to reduce testosterone to castrated level (consensus testosterone castration level< 50 ng/dL). Instead, the present theory emphasizes ‘deep castration suppression’ (maximal control) and ‘long-term stability’ (dynamic stability), which also considers preserving the necessary, appropriate, sustained physiological requirement of testosterone. This study established the aPC treatment concept of changing from ‘testosterone castration’ to ‘testosterone maximal control’, promoting the development of standardized and individualized treatment mode for aPC patients. The study established a schematic diagram of testosterone management process, see Figure 5 .

A nadir testosterone level of 10 ng/dL serves as a significant predictor of tumor progression and survival in patients with advanced PCa undergoing ADT. Challenging the conventional castration threshold of 50 ng/dL, our findings establish 10 ng/dL as a more discriminative and clinically relevant boundary for evaluating PCa outcomes. These results advocate for a refined definition of maximal testosterone control, moving beyond traditional castration benchmarks, to better reflect the level of testosterone control required to optimize prognosis in advanced PCa.