Abstract
Purpose
Continuous androgen deprivation therapy (cADT) remains the standard treatment for advanced prostate cancer; however, it is associated with morbidity and a reduced quality of life. Intermittent ADT (iADT) is a potential strategy to mitigate these effects; however, the optimal scheduling for iADT remains unclear. This study evaluates the testosterone (T) suppression efficacy and the oncologic safety of different iADT schedules in patients with biochemically recurrent (BCR) prostate cancer.
Methods
We conducted a retrospective analysis of 119 men with castrate T levels (<20 ng/dL) and stable prostate-specific antigen (PSA) nadirs following cADT for BCR after radical prostatectomy or radiotherapy. Patients underwent iADT using one of three schedules: 1-on/1-off, 1-on/2-off, or 3-on/3-off months. We tracked serum T and PSA kinetics, and incidence rates of T breakthrough during a median follow-up of 12.0 months. Predictors of T breakthrough were investigated.
Results
The three groups had no differences in baseline clinicopathological and laboratory features. The 1-on/1-off regimen effectively suppressed serum T for up to six months, while 1-on/2-off and 3-on/3-off schedules were associated with higher incidences of T breakthrough (P = 0.002). Despite corresponding PSA rises, no radiographic progression was observed across groups. Predictors of successful T suppression included 1-on/1-off schedule and lower baseline T at iADT initiation.
Conclusion
A 1-on/1-off iADT schedule may offer a clinically viable alternative to cADT in maintaining successful T suppression. iADT may be particularly useful in patients seeking to reduce ADT side effects. Further studies are needed to validate these findings and optimize iADT protocols.
Keywords: Androgen deprivation therapy, Biochemical recurrence, Prostatic Neoplams, Testosterone
1. Introduction
Androgen deprivation therapy (ADT) remains the cornerstone systemic treatment for recurrent and advanced prostate cancer (PCa), exploiting the androgen dependence of prostate tumor cells.1,2 Testosterone (T) suppression via luteinizing hormone-releasing hormone agonists or antagonists reduces tumor proliferation and induces apoptosis, thereby controlling disease progression.3 However, chronic T deprivation leads to a spectrum of adverse effects. These include fatigue, sarcopenia, insulin resistance, adverse lipid profiles, contributing to metabolic syndrome, increased cardiovascular morbidity, bone loss, cognitive decline, and sexual dysfunction 3, 4, 5, 6. The cumulative burden of these toxicities can significantly compromise patient adherence and quality of life, particularly in men with indolent disease or prolonged survival expectations.
Intermittent androgen deprivation therapy (iADT) was developed as a strategy to minimize these toxicities while preserving oncologic efficacy. iADT involves cyclic administration of ADT with defined treatment “on” periods followed by “off” intervals, allowing partial T recovery.7 Randomized clinical trials in metastatic and locally advanced PCa have shown that iADT provides comparable overall survival to continuous ADT (cADT), improving quality-of-life domains, including sexual function, physical vigor, and emotional well-being.8,9 Moreover, iADT may reduce the risk of metabolic and cardiovascular complications by limiting cumulative androgen deprivation exposure. iADT has also been observed to delay the onset of castration-resistant compared to cADT, in patients with nonmetastatic disease.10 Despite these promising findings, widespread adoption of iADT is limited by a lack of consensus regarding optimal scheduling, prostate-specific antigen (PSA) thresholds for treatment initiation and cessation, and the duration of cADT induction.
The biological rationale for iADT lies in its reversible suppression of serum T, allowing its recovery during off-treatment periods. However, the dynamics of T suppression and recovery are influenced by various patient-specific factors and treatment regimens. T breakthrough may reactivate androgen receptor signaling and tumor proliferation, potentially leading to earlier hormonal escape and disease progression 11, 12, 13. Furthermore, PSA kinetics during iADT may not directly correlate with fluctuations in T levels, complicating clinical monitoring and treatment decision-making. The relationship between T recovery, PSA dynamics, and treatment schedule remains incomplete, particularly in patients with biochemical recurrence (BCR), where the disease biology and treatment goals differ from metastatic settings.11
Current literature on iADT primarily addresses metastatic hormone-sensitive or castration-resistant PCa, with comparatively limited data focusing on nonmetastatic BCR.7,14 Additionally, published iADT protocols show variability in their design, including differences in induction duration, PSA thresholds for initiating off-treatment periods, and criteria for reinitiating ADT, limiting cross-study comparisons and guideline development. Identifying predictors of T breakthrough and hormonal escape within various iADT regimens is critical to optimizing patient selection and treatment personalization.
In this retrospective study, we compare the efficacy of T suppression and PSA kinetics across three distinct iADT schedules in patients with BCR following definitive local therapy. We assess the incidence and timing of T breakthrough, observe PSA kinetics during on- and off-treatment phases, and identify factors associated with T breakthrough. Our findings aim to elucidate how different iADT protocols influence serum T control, support clinical decision-making, and refine iADT strategies.
2. Materials and methods
2.1. Study cohort
We retrospectively reviewed the clinicopathological and laboratory features of 119 men with PCa who were transitioned to iADT following a course of cADT for BCR after definitive treatment with radical prostatectomy (RP), followed by salvage radiation therapy (RT) or RT. The BCR was defined as a serum PSA level ≥0.2 ng/mL following RP and a PSA rise of ≥2.0 ng/mL above the post-treatment nadir following RT. Patients who achieved castrate serum T levels (<20 ng/dL) and had responded with a PSA nadir lower than 0.2 ng/mL in cases submitted to salvage RT after RP and lower than 0.4 ng/mL in cases submitted to primary RT were candidates for iADT transition and were selected for analysis. The PSA rebound was considered to be a PSA above these levels during iADT.
Patients received iADT according to one of three predefined regimens: 1 month on/1 month off (n = 59), 1 month on/2 months off (n = 39), or 3 months on/3 months off (n = 21). Treating physicians determined regimen selection based on clinical judgment and patient preference. Serum PSA and T levels were monitored throughout treatment cycles. A T breakthrough was defined as any serum T measurement >20 ng/dL during iADT.
2.2. Study endpoints
The primary study endpoint was the change in serum T levels obtained at each injection time point. Secondary endpoints were the proportion of patients experiencing T breakthrough and predictors associated with T breakthrough.
2.3. Statistical analyses
Comparative analyses of clinicopathological and laboratory variables between iADT regimens were conducted using the chi-square test for categorical variables and analysis of variance (ANOVA) for continuous variables. The Kruskal–Wallis or Mann–Whitney U tests were used to compare continuous data with the control group. The Cox proportional hazards regression analysis evaluated predictions associated with T breakthrough-free survival. Variables assessed included: age, body mass index (BMI), PSA level, International Society of Urological Pathology (ISUP) grade group, T stage, duration of prior cADT, baseline T level at iADT initiation, and iADT schedule. The multivariate Cox regression model included variables with a P value <0.005 in univariate analysis.
All statistical analyses were performed using the Statistical Package for the Social Sciences (version 16.0) and Power Analysis and Sample Size (version 15). This study was approved by our institutional ethics committee (2024-0195-001) after a reviewing of the protocols employed. All study procedures complied with the 1946 Declaration of Helsinki principles and its 2008 update.
3. Results
3.1. Patient characteristics
Baseline characteristics, including age, body mass index, body surface area, PSA level at diagnosis, ISUP grade group, tumor, node, metastatsis (TNM) stage, prior treatment modalities, duration of cADT prior to iADT transition, and laboratory values, including serum T at iADT transition, were comparable across groups (all P > 0.05) (Table 1).
Table 1.
Clinicopathological features and laboratory values of the overall cohort, stratified by the type of iADT
| Overall (n = 119) | iADT type |
||||
|---|---|---|---|---|---|
| 1-on, 1-off (n = 59) | 1-on, 2-off (n = 39) | 3-on, 3-off (n = 21) | P | ||
| Age (year) | 69.0 (61.5–75.0) | 68.0 (60.7–75.0) | 69.5 (62.0–76.8) | 65.0 (62.0–74.0) | 0.737 |
| Body mass index (kg/m2) | 24.9 (23.5–26.6) | 24.9 (23.3–26.5) | 24.7 (23.1–26.3) | 26.3 (24.2–27.3) | 0.348 |
| Body surface area (m2) | 1.83 (1.74–1.91) | 1.82 (1.73–1.94) | 1.83 (1.74–1.88) | 1.84 (1.80–1.98) | 0.334 |
| PSA at diagnosis (ng/mL) | 8.7 (6.8–16.0) | 8.31 (6.5–17.8) | 8.85 (6.78–12.0) | 10.0 (8.1–19.6) | 0.468 |
| ISUP grade group | |||||
| 1–3 | 75 (63.0%) | 35 (59.3%) | 29 (74.4%) | 11 (52.4%) | 0.109 |
| 4 | 28 (23.5%) | 13 (22.0%) | 8 (20.5%) | 7 (33.3%) | 0.165 |
| 5 | 16 (13.5%) | 11 (18.7%) | 2 (5.1%) | 3 (14.3%) | 0.658 |
| T Stage | |||||
| ≤T2 | 39 (32.8%) | 16 (27.1%) | 17 (43.6%) | 6 (28.6%) | 0.699 |
| ≥T3 | 80 (67.2%) | 43 (72.9%) | 22 (56.4%) | 15 (71.4%) | 0.651 |
| N stage (N1) | 7 (0.06%) | 4 (0.07%) | 2 (0.05%) | 1 (0.05%) | 0.562 |
| M stage (M1) | 6 (0.05%) | 5 (0.08%) | 1 (0.03%) | 0 (0.0%) | 0.758 |
| Curative treatment | |||||
| Radical prostatectomy | 103 (86.6%) | 49 (83.1%) | 36 (92.3%) | 18 (85.7%) | 0.453 |
| Radiation therapy | 16 (13.4%) | 10 (16.9%) | 3 (7.7%) | 3 (14.3%) | 0.139 |
| Period of cADT before iADT | 18.0 (6.0–26.0) | 23.5 (7.8–32.3) | 11.0 (3.0–24.0) | 16.0 (9.0–30.0) | 0.166 |
| Leuprolide dose | |||||
| 3.75 mg | 57 (47.9%) | 28 (47.5%) | 29 (74.4%) | 0 (0.0%) | 0.468 |
| 7.5 mg | 41 (34.5%) | 31 (52.5%) | 10 (25.6%) | 0 (0.0%) | 0.651 |
| 11.25 mg | 21 (17.6%) | 0 (0.0%) | 0 (0.0%) | 21 (100.0%) | <0.01 |
| Laboratory values1) | |||||
| PSA (ng/mL) | 0.02 (0.01–0.09) | 0.04 (0.01–0.10) | 0.01 (0.01–0.04) | 0.02 (0.01–0.65) | 0.287 |
| Testosterone (ng/dL) | 2.59 (2.59–8.08) | 2.59 (2.59–7.06) | 2.74 (2.59–8.94) | 2.89 (2.59–11.3) | 0.983 |
| Hemoglobin (g/dL) | 13.7 (12.7–14.5) | 13.9 (12.7–14.7) | 13.8 (12.7–14.7) | 12.9 (12.4–14.0) | 0.369 |
| Hematocrit (%) | 40.9 (37.2–43.2) | 41.1 (39.3–43.5) | 41.0 (37.4–43.3) | 39.5 (36.9–41.5) | 0.446 |
| WBC ccount (μL) | 5630 (4630–7235) | 5340 (4570–7225) | 5610 (4495–6757) | 6410 (5260–7980) | 0.399 |
| Creatinine (mg/dL) | 0.87 (0.77–0.99) | 0.88 (0.78–0.99) | 0.87 (0.77–0.96) | 0.78 (0.72–0.99) | 0.658 |
| AST (IU/L) | 25.0 (21.5–29.0) | 25.0 (22.0–29.0) | 24.5 (20.0–28.3) | 23.0 (20.5–28.5) | 0.664 |
| ALT (IU/L) | 21.0 (16.0–28.5) | 20.5 (15.8–31.3) | 21.5 (17.0–27.3) | 22.0 (14.5–26.5) | 0.692 |
| Alkaline phosphatase (IU/L) | 65.0 (54.0–86.0) | 62.5 (54.0–80.5) | 66.5 (53.5–86.3) | 68.0 (54.5–87.5) | 0.807 |
Values are presented in number (%) and median (IQR).
ALT, alanine aminotransferase;AST, aspartate aminotransferase;CI, confidence interval; cADT, continuous; androgen deprivation therapy; HR, hazards ratio; iADT, intermittent androgen deprivation therapy; ISUP, International Society of Urological Pathology;PSA, prostate-specific antigen; WBC, white blood cell.
Values obtained at initiation of iADT.
3.2. Changes in serum T levels and T breakthrough
Fig. 1 depicts the changes in serum T levels according to each specific iADT regimen. The results show that the 1-on/1-off regimen offered the most adequate T suppression compared to the other iADT schedules.
Fig. 1.
Changes in serum testosterone levels following intermittent ADT, stratified by treatment schedule. ADT, androgen deprivation therapy.
T breakthrough incidence and T breakthrough-free survival are presented in Table 2. In the overall cohort, T breakthrough was observed in 87 patients (73.1%). The incidence of T breakthrough was significantly lower in the 1-on/1-off group (57.6%) compared to 1-on/2-off (89.7%) and 3-on/3-off (85.7%) groups (P = 0.002). Median T breakthrough-free survival was significantly longer in the 1-on/1-off group (7.0 months), compared to 2.0 and 3.0 months in the 1-on/2-off and 3-on/3-off groups, respectively (P < 0.001). The T breakthrough-free survival rates at 12 months were 64.8%, 35.2%, and 0% in the 1-on/1-off, 1-on/2-off, and 3-on/3-off groups, respectively (P < 0.001).
Table 2.
Testosterone breakthrough-free survival and oncological outcomes, stratified by the type of iADT
| Overall (n = 119) | iADT type |
||||
|---|---|---|---|---|---|
| 1-on, 1-off (n = 59) | 1-on, 2-off1) (n = 39) | 3-on, 3-off1) (n = 21) | P value2) | ||
| T breakthrough, n (%) | 87 (73.1%) | 34 (57.6%) | 35 (89.7%)4) | 18 (85.7%)4) | 0.002 |
| T breakthrough-free survival, 12 months (%) | 43.7% | 64.8% | 35.2%3) | 0.0%4) | <0.001 |
| Median (IQR) T breakthrough period (months) | 4.0 (3.5–4.5) | 7.0 (3.5–9.0) | 2.0 (2.0–2.0)4) | 3.0 (3.0–3.0)4) | <0.001 |
| PSA rebound, n (%) | 38 (31.9%) | 13 (22.0%) | 17 (43.6%) | 8 (38.1%) | 0.089 |
| Radiographic progression, n (%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | NA |
| Follow-up period (months) | 12.0 (8.5–14.0) | 9.5 (8.0–14.0) | 12.0 (10.0–15.0) | 14.0 (11.0–17.0)∗ | <0.001 |
Values are presented in number (%) and median (IQR).
iADT, intermittent androgen deprivation therapy; IQR, interquartile range; NA, not applicable; PSA, prostate-specific antigen; T, Ttstosterone.
Mann–Whitney U test was used to compare data with the 1-on, 1-off group.
p values in Kruskal–Wallis test.
P < 0.025.
P < 0.005 for the comparison with the 1-on, 1-off group.
3.3. Oncological outcome
In the overall cohort, PSA rebound was observed in 38 (31.9 %) patients, with no statistically significant differences between iADT schedules (P = 0.089). Despite T breakthroughs and PSA rebounds, no patient exhibited radiographic progression during the median follow-up period of 12.0 months (Table 2).
3.4. Predictors of T breakthrough
Multivariate Cox proportional hazards regression analysis for identifying predictors of T breakthrough is presented in Table 3. Among laboratory values at iADT initiation, a higher baseline T level was independently associated with an increased risk of T breakthrough (hazard ratio [HR] = 1.003, 95% confidence interval [CI]: 1.001–1.006, P = 0.007). For the iADT schedule, the 1-on/2-off (HR = 3.356, 95% CI: 1.584–7.110, P = 0.002) and the 3-on/3-off (HR = 2.154, 95% CI: 1.358–3.186, P < 0.001) schedules were associated with an increased risk of T breakthrough, compared to the 1-on/1-off iADT schedule as reference. No other clinicopathological or laboratory variables including age, BMI, PSA level, ISUP grade, T stage, or duration of prior cADT, were associated with the risk of T breakthrough.
Table 3.
Cox-regression models evaluating risk factors associated with serum testosterone breakthrough (>20 ng/dL)
| Univariate |
Multivariate |
|||||
|---|---|---|---|---|---|---|
| HR | 95% CI | P | HR | 95% CI | P | |
| Age | 0.993 | 0.966–1.021 | 0.640 | |||
| Body mass index | 1.025 | 0.936–1.122 | 0.594 | |||
| Body surface area | 1.208 | 0.180–8.099 | 0.845 | |||
| Laboratory values1) | ||||||
| PSA | 1.006 | 0.540–1.873 | 0.984 | |||
| Testosterone | 1.003 | 1.001–1.005 | 0.001 | 1.003 | 1.001–1.006 | 0.007 |
| Hemoglobin | 1.083 | 0.915–1.281 | 0.355 | |||
| Hematocrit | 1.035 | 0.981–1.092 | 0.208 | |||
| WBC ccount | 0.976 | 0.890–1.071 | 0.614 | |||
| Creatinine | 0.628 | 0.151–2.607 | 0.521 | |||
| Aspartate aminotransferase | 0.999 | 0.968–1.031 | 0.946 | |||
| Alanine aminotransferase | 1.005 | 0.987–1.023 | 0.595 | |||
| Alkaline phosphatase | 1.004 | 0.994–1.013 | 0.477 | |||
| Stage | ||||||
| ≥T3 vs. ≤T2 | 0.794 | 0.475–1.328 | 0.380 | |||
| N1 vs. N0 | 0.717 | 0.175–2.941 | 0.644 | |||
| M1 vs. M0 | 0.824 | 0.201–3.387 | 0.789 | |||
| ISUP grade group | ||||||
| ≥4 | 1 | Reference | ||||
| ≤3 | 0.769 | 0.467–1.266 | 0.302 | |||
| Type of iADT | ||||||
| 1-on, 1-off | 1 | Reference | 1 | Reference | ||
| 1-on, 2-off | 3.463 | 1.524–9.021 | 0.005 | 3.356 | 1.584–7.110 | 0.002 |
| 3-on, 3-off | 1.798 | 1.141–3.631 | 0.002 | 2.154 | 1.358–3.186 | <0.001 |
| Leuprolide dose | ||||||
| 3.75 mg | 1 | Reference | ||||
| 7.5 mg | 1.012 | 0.554–1.850 | 0.969 | |||
| 11.25 m | 1.015 | 0.978–1.033 | 0.264 | |||
| Period of cADT before iADT | 0.997 | 0.982–1.012 | 0.667 | |||
| Curative treatment | ||||||
| Radical prostatectomy | 1 | Reference | ||||
| Radiation therapy | 0.800 | 0.116–6.102 | 0.863 | |||
cADT, continuous; androgen deprivation therapy; CI, confidence interval; HR, hazards ratio; iADT, intermittent androgen deprivation therapy; ISUP, International Society of Urological Pathology;PSA, prostate-specific antigen; WBC, white blood cell.
Values obtained at initiation of iADT.
4. Discussion
This study represents the first real-world analysis to evaluate the impact of different iADT interval lengths on T dynamics in patients who had previously achieved durable castrate T levels and PSA nadirs with cADT. Among the regimens analyzed, the 1-on/1-off schedule exhibited the most robust T suppression, yielding significantly lower rates of T breakthrough and a 12-month breakthrough-free survival of 64.8%. In contrast, extended off-treatment intervals in the 1-on/2-off and 3-on/3-off groups were associated with markedly higher breakthrough rates, with T breakthrough-free survival declining to 35% and 0%, respectively.
Importantly, despite fluctuations in T and PSA rebounds in the longer off-cycle groups, no radiographic progression was observed during the follow-up period, supporting the oncologic safety of iADT in appropriately selected, nonmetastatic patients. This observation aligns with prior randomized data including the PR7 trial, which demonstrated comparable survival outcomes between intermittent and continuous ADT and a delay in progression to castration-resistant disease in the intermittent arm.12 The timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]) trial similarly reported no immediate survival disadvantage to deferred ADT in men with rising PSA, suggesting that modest delays or fluctuations in T may be oncologically acceptable in nonmetastatic disease.14
Testosterone suppression remains a foundational goal in systemic PCa therapy, and the achievement of castrate T levels is recognized as a critical therapeutic target, particularly in the context of androgen-sensitive disease.15 In this study, the 1-on/1-off iADT regimen effectively maintained castrate levels of T for a median of six to seven months. This sustained suppression is likely attributable to shorter off-treatment intervals that may attenuate hypothalamic–pituitary–gonadal axis reactivation, thereby reducing the stimulus for Leydig cell-mediated T recovery. Salciccia, et al. compared iADT versus cADT with respect to Castration-resistant prostate cancer (CRPC) progression in patients presenting with nonmetastatic BCR following definitive treatments.16 Although the type of ADT administration did not influence the development of M1CRPC, iADT was associated with a delay in the onset of M0CRPC. Although the biological mechanism underlying this observation is unclear, it partly aligns with prior pharmacodynamic studies supporting shorter ADT cycling to reduce T fluctuations and maintain biochemical control.9,13,15 Minimizing T fluctuations through shorter ADT cycling may prevent intermittent surges in androgen receptor activation, which have been hypothesized to contribute to clonal selection and adaptation toward castration-resistance.17 Overall, our observation supports the biologic feasibility and clinical utility of a tightly cycled 1-on/1-off iADT schedule, offering a potential strategy to prolong the efficacy of ADT while delaying androgen resistance, which could influence the natural history of disease progression.
Multivariable analysis identified both iADT regimen and baseline T level at iADT transition as independent predictors of T breakthrough. Lower baseline T levels were associated with more durable suppression, implying that residual Leydig cell function influences treatment durability.5 These findings suggest the potential for personalizing iADT schedules based on baseline hormonal profiles. For instance, patients with higher initial T may benefit from shorter off-cycles to mitigate the risk of incomplete T suppression and T breakthrough.
The 1-on/1-off schedule may provide an optimal balance between disease control and mitigation of treatment-related adverse events. ADT is associated with well-documented morbidity including metabolic dysfunction, bone loss, sexual and cognitive impairment, and fatigue 4,18, 19, 20, 21. Several studies have generally demonstrated that iADT modestly improves quality of life outcomes, especially during off-treatment periods when T partially recovers.8,18 However, other studies have shown no substantial difference in tolerability and quality-of-life profiles between intermittent and continuous regimens.1 Taken together, these discrepancies suggest that the benefit of iADT likely depends on individual patient factors including off-treatment period length and time to recovery of T levels. Although patient-reported outcomes were not collected in our study, the maintenance of biochemical control with shorter cycling intervals suggests the potential for symptom relief without compromising oncologic safety.
This study also contributes to the evolving definition of failure in the iADT context. While incomplete T suppression and T breakthrough are often viewed as surrogates for therapeutic failure, their prognostic relevance remains uncertain in the absence of radiographic or symptomatic progression. PSA kinetics are often sensitive to transient T changes, but may not accurately reflect disease activity.22 Given the observed short-term T level fluctuations during iADT in our study, iADT protocols will require careful monitoring and serial assessments to ensure continued oncologic safety. Further research is needed to better correlate T dynamics with long-term endpoints such as metastasis-free survival and time to castration resistance.
A key strength of this study is the standardized assessment of serum T and PSA levels at strictly fixed intervals throughout the follow-up period. Moreover, the homogeneous disease population, consisting exclusively of nonmetastatic patients with comparable baseline characteristics, allowed for the isolated assessment of the impact of ADT scheduling on T kinetics. However, several limitations must be acknowledged. First, the retrospective design and nonrandomized treatment selection introduce potential bias. Treatment intervals were chosen based on physician judgment and patient preference, and the rationale for choosing a particular regimen was not standardized. The resulting imbalance in duration of cADT and limited follow-up duration precludes conclusions regarding long-term oncologic safety. Second, the 3-on/3-off cohort was relatively small, limiting statistical power for meaningful subgroup comparisons. Third, quality-of-life data were not collected, which precludes conclusions regarding symptomatic benefit. Finally, none of the patients developed castration resistance during follow-up, which precludes any conclusions regarding the potential benefit of iADT in delaying the onset of CRPC. Nevertheless, we achieved the primary objective of this study, which was to compare T dynamics across different iADT schedules, offering real-world data that shorter iADT cycles, particularly the 1-on/1-off regimen, may offer durable T suppression without radiologic compromise. These findings support a more individualized approach to hormonal therapy, wherein treatment intensity and interval are tailored to baseline hormonal status and patient preference. Prospective trials are warranted to validate these results, identify predictive biomarkers, and establish evidence-based iADT protocols optimized for both oncologic efficacy and the maintenance of quality of life.
5. Conclusions
This retrospective analysis demonstrates that a 1-on/1-off iADT schedule achieves more durable T suppression and significantly lower rates of T breakthrough compared to regimens with prolonged off-treatment intervals in patients with prior stable castrate T levels on cADT. Despite fluctuations in T and PSA kinetics, no patients developed radiographic progression, indicating that iADT can be oncologically safe in this setting. Baseline T levels and iADT schedule emerged as independent predictors of breakthrough, highlighting the importance of individualized regimen selection. The 1-on/1-off approach may offer an optimal balance between treatment efficacy and quality of life by minimizing androgen exposure while preserving disease control. These findings support the clinical utility of shorter-cycle iADT and underscore the need for prospective studies to further define optimal scheduling and patient selection.
Author contributions
Conceptualization: Tae Jin Kim and Kyo Chul Koo. Data curation and formal analysis: Jeong Hyun Lee, Tae Jin Kim and Byung Ha Chung. Funding acquisition: Kyo Chul Koo. Investigation: Tae Jin Kim and Kyo Chul Koo. Methodology: Jeong Hyun Lee, Tae Jin Kim, and Kyo Chul Koo. Project administration: Tae Jin Kim. Resource: Kyo Chul Koo. Software: Tae Jin Kim. Supervision: Kyo Chul Koo. Validation: Tae Jin Kim. Visualization: Tae Jin Kim and Kyo Chul Koo. Writing - original draft: Jeong Hyun Lee and Tae Jin Kim. Writing - review & editing: Tae Jin Kim, Byung Ha Chung, Sung Un Bang, and Kyo Chul Koo. Approval of final manuscript: all authors.
This study has not been previously published elsewhere.
Conflicts of interest
All authors have no conflict of interest. Given his role as Editorial Board Member of Prostate International, Byung Ha Chung and Editorial Board Member of Prostate International, Kyo Chul Koo had no involvement in the peer review of this article and had no access to information regarding its peer review.
Acknowledgments
None.
Contributor Information
Kyo Chul Koo, Email: gckoo@yuhs.ac.
Tae Jin Kim, Email: tjkim81@cha.ac.kr.
References
- 1.Schulman C., Cornel E., Matveev V., Tammela TL., Schraml J., Bensadoun H., et al. Intermittent versus continuous androgen deprivation therapy in patients with relapsing or locally advanced prostate cancer: a phase 3b randomised study (ICELAND) Eur Urol. 2016;69:720–727. doi: 10.1016/j.eururo.2015.10.007. [DOI] [PubMed] [Google Scholar]
- 2.Yamada Y., Sakamoto S., Tsujino T., Saito S., Sato K., Nishimura K., et al. Clinical significance of primary tumor progression in metastatic hormone-sensitive prostate cancer. Prostate Int. 2025;13:60–66. doi: 10.1016/j.prnil.2024.11.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Sayyid R.K., Sayyid A.K., Klaassen Z., Fadaak K., Goldberg H., Chandrasekar T., et al. Testosterone responders to continuous androgen deprivation therapy show considerable variations in testosterone levels on followup: implications for clinical practice. J Urol. 2018;199:251–256. doi: 10.1016/j.juro.2017.07.078. [DOI] [PubMed] [Google Scholar]
- 4.Tzortzis V., Samarinas M., Zachos I., Oeconomou A., Pisters LL., Bargiota A., et al. Adverse effects of androgen deprivation therapy in patients with prostate cancer: focus on metabolic complications. Hormones (Basel) 2017;16:115–123. doi: 10.14310/horm.2002.1727. [DOI] [PubMed] [Google Scholar]
- 5.Tombal B., Cornel E.B., Persad R., Stari A., Gómez Veiga F., Schulman C., et al. Clinical outcomes and testosterone levels following continuous androgen deprivation in patients with relapsing or locally advanced prostate cancer: a post hoc analysis of the ICELAND study. J Urol. 2017;198:1054–1060. doi: 10.1016/j.juro.2017.05.072. [DOI] [PubMed] [Google Scholar]
- 6.Di H., Wen Y., Wang J., Wang J., Wang Y., Li Y., et al. The impact of obesity and sexual behavior on prostate cancer risk is mediated by testosterone levels: a mendelian randomization study and mediation analysis. Prostate Int. 2024;12:96–103. doi: 10.1016/j.prnil.2024.03.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Klotz L. Intermittent versus continuous androgen deprivation therapy in advanced prostate cancer. Curr Urol Rep. 2013;14:159–167. doi: 10.1007/s11934-013-0325-x. [DOI] [PubMed] [Google Scholar]
- 8.Salonen A.J., Taari K., Ala-Opas M., Viitanen J., Lundstedt S., Tammela TL., et al. Advanced prostate cancer treated with intermittent or continuous androgen deprivation in the randomised FinnProstate study VII: quality of life and adverse effects. Eur Urol. 2013;63:111–120. doi: 10.1016/j.eururo.2012.07.040. [DOI] [PubMed] [Google Scholar]
- 9.Tunn U.W., Canepa G., Kochanowsky A., Kienle E. Testosterone recovery in the off-treatment time in prostate cancer patients undergoing intermittent androgen deprivation therapy. Prostate Cancer Prostatic Dis. 2012;15:296–302. doi: 10.1038/pcan.2012.12. [DOI] [PubMed] [Google Scholar]
- 10.Crook J.M., O’Callaghan C.J., Duncan G., Dearnaley DP., Higano CS., Horwitz EM., et al. Intermittent androgen suppression for rising PSA level after radiotherapy. N Engl J Med. 2012;367:895–903. doi: 10.1056/NEJMoa1201546. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Nikitas J., Ong W.L., Carrier N., Romero T., Millar J., Steinberg ML., et al. Prostate-specific antigen response to androgen deprivation therapy in the neoadjuvant setting for high-risk prostate adenocarcinoma (PIRANHA): pooled analysis of two randomized clinical trials. Int J Radiat Oncol Biol Phys. 2024;119:826–831. doi: 10.1016/j.ijrobp.2023.12.022. [DOI] [PubMed] [Google Scholar]
- 12.Klotz L., O’Callaghan C., Ding K., Toren P., Dearnaley D., Higano CS., et al. Nadir testosterone within first year of androgen-deprivation therapy (ADT) predicts for time to castration-resistant progression: a secondary analysis of the PR-7 trial of intermittent versus continuous ADT. J Clin Oncol. 2015;33:1151–1156. doi: 10.1200/JCO.2014.58.2973. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Ma T.M., Sun Y., Malone S., Roach M., 3rd, Dearnaley D., Pisansky TM., et al. Sequencing of androgen-deprivation therapy of short duration with radiotherapy for nonmetastatic prostate cancer (SANDSTORM): a pooled analysis of 12 randomized trials. J Clin Oncol. 2023;41:881–892. doi: 10.1200/JCO.22.00970. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Duchesne G.M., Woo H.H., Bassett J.K., Bowe SJ., D’Este C., Frydenberg M., et al. Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial. Lancet Oncol. 2016;17:727–737. doi: 10.1016/S1470-2045(16)00107-8. [DOI] [PubMed] [Google Scholar]
- 15.Sasaki H., Miki K., Tashiro K., Mori K., Urabe F., Fukuokaya W., et al. Differences in sex hormone recovery profile after cessation of 12-week gonadotropin-releasing hormone antagonist versus agonist therapy. Andrology. 2022;10:270–278. doi: 10.1111/andr.13107. [DOI] [PubMed] [Google Scholar]
- 16.Salciccia S., Frisenda M., Tufano A., Di Pierro G., Bevilacqua G., Rosati D., et al. Intermittent versus continuous androgen deprivation therapy for biochemical progression after primary therapy in hormone-sensitive nonmetastatic prostate cancer: comparative analysis in terms of CRPC-M0 progression. Clin Genitourin Cancer. 2024;22:74–83. doi: 10.1016/j.clgc.2023.08.008. [DOI] [PubMed] [Google Scholar]
- 17.Mostaghel E.A., Nelson P.S. Intracrine androgen metabolism in prostate cancer progression: mechanisms of castration resistance and therapeutic implications. Best Pract Res Clin Endocrinol Metabol. 2008;22:243–258. doi: 10.1016/j.beem.2008.01.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Bruchovsky N., Klotz L., Crook J., Phillips N., Abersbach J., Goldenberg SL., et al. Quality of life, morbidity, and mortality results of a prospective phase II study of intermittent androgen suppression for men with evidence of prostate-specific antigen relapse after radiation therapy for locally advanced prostate cancer. Clin Genitourin Cancer. 2008;6:46–52. doi: 10.3816/CGC.2008.n.008. [DOI] [PubMed] [Google Scholar]
- 19.Joung J.Y., Jeong I.G., Kang S.G., Ko YH., Koo KC., Kim KH., et al. Establishing consensus recommendations for metastatic hormone-sensitive prostate cancer in South Korea: a modified Delphi study. Investig Clin Urol. 2025;66:416–430. doi: 10.4111/icu.20250147. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Cherrier M.M., Aubin S., Higano C.S. Cognitive and mood changes in men undergoing intermittent combined androgen blockade for non-metastatic prostate cancer. Psychooncology. 2009;18:237–247. doi: 10.1002/pon.1401. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Kyaw L., Lim Q.Y., Law Y.X.T., Ong CSH., Loke WT., Chiong E., et al. Cardiovascular risks of Asian patients on androgen-receptor-targeted agents for prostate cancer: a systematic review and meta-analysis. Prostate Int. 2024;12:186–194. doi: 10.1016/j.prnil.2024.07.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.D’Amico A.V., Chen M.H., Roehl K.A., Catalona WJ. Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med. 2004;351:125–135. doi: 10.1056/NEJMoa032975. [DOI] [PubMed] [Google Scholar]