High 11-Ketotestosterone Linked to Shorter Time to Castration Resistance in Recurrent Nonmetastatic Prostate Cancer

Abstract

Purpose:

The contribution of 11-oxygenated androgens to the progression of lethal prostate cancer (PCa) remains unresolved. We hypothesized that evaluating circulating levels of 11-oxygenated androgens, such as the androgen receptor agonist 11-ketotestosterone (11KT), could serve as a potential predictor of the onset of castration-resistant PCa (CRPC).

Materials and Methods:

We used mass spectrometry to quantify 11-oxygenated androgens in postoperative plasma samples acquired from 145 patients who subsequently received androgen deprivation therapy for biochemical recurrence and achieved castrated testosterone levels. Kaplan-Meier survival analyses and multivariable Cox models were used to investigate relationships between steroids and CRPC.

Results:

Of 145 patients, 31 developed CRPC with a median time to CRPC of 57 months. 11-Oxygenated androgen levels were unaffected by androgen deprivation therapy, which stands in contrast to the observed changes in testosterone and other steroids. 11KT was the most abundant androgen but was not linked to clinical features. Kaplan-Meier analysis revealed that 11KT levels above the median of 273 pg/mL were associated with a shorter time to CRPC (P = .03). In multivariable analyses, this was supported with an adjusted HR of 2.17 (95% CI, 0.99-4.71; P = .05).

Conclusions:

11KT is a key component of the hormonal profile predictive of earlier onset of CRPC. Enhancing our understanding of the specific role of 11KT in the progression to CRPC could help optimize hormonal therapy for castration-sensitive patients with PCa and CRPC.

Prostate cancer (PCa) is the most common cancer in men.¹ PCa progression is driven by androgens, and targeting the androgen receptor (AR) axis is the fundamental approach to treatment—even in the context of advanced castration-resistant PCa (CRPC).^2,3 Despite the ability to suppress testosterone (T) levels through androgen deprivation therapy (ADT), cancer cells maintain the necessary enzymatic machinery to convert circulating adrenal androgens into potent, tumorigenic androgens.⁴ This process favors the development of castration-resistant cell populations.^5,6 Consistent with this, among patients with recurrent nonmetastatic PCa participating in the PR-7 trial and receiving continuous ADT, it was observed that circulating T, estrogens, and dehydroepiandrosterone (DHEA) were indeed linked to a shorter time to CRPC.^7,8 For advanced cases of castration-sensitive metastatic disease, this observation was reinforced by numerous phase 3 clinical studies, which have demonstrated significant responses and improved survival associated with inhibitors of AR pathways.^9-11 Based on these studies, it is now widely recognized that the importance of local steroid biotransformation is significant for patients with localized and advanced disease under ADT, influencing androgen exposure of PCa cells.^5,12 The relevance is further illustrated by polymorphism of the gene HSD3B1 (1234C), the protein product of which is involved in androgen biosynthesis and results in an adrenal-permissive phenotype that accelerates the development of CRPC.¹³

JU Insight

• Study Need and Importance

• Castration-sensitive prostate cancer often transitions to the castration-resistant stage (CRPC), the lethal form of the disease. The role of circulating androgens in cancer progression remains unclear, especially for the noncanonical 11-oxygenated androgens like the androgen receptor agonist 11-ketotestosterone (11KT). This study aimed to determine whether levels of 11-oxygenated androgens could predict CRPC onset in patients undergoing androgen deprivation therapy (ADT) for recurrent nonmetastatic disease.

• What We Found

• From the prospective PROCURE cohort, we studied 145 recurrent nonmetastatic patients who had available blood samples under ADT to quantify steroids using mass spectrometry. Among them, 31 progressed to CRPC, with a median time of 57 months. Unlike testosterone and other steroids, 11-oxygenated androgens were unaffected by ADT. The androgen receptor agonist 11KT was the most abundant circulating androgen, and elevated levels were significantly associated with earlier progression to CRPC.

• Limitations

• Limitations include the relatively small number of patients and CRPC events, despite the extensive follow-up period of 99 months from relapse to CRPC occurrence. Additional studies are therefore needed to validate the findings.

• Interpretation for Patient Care

• Our findings indicate that 11KT is the predominant circulating androgen in men on ADT, with higher levels linked to sooner progression to CRPC in recurrent nonmetastatic prostate cancer. Monitoring 11KT levels in patients under ADT might help identify patients at higher risk of progression to CRPC.

A class of noncanonical androgens, named 11-oxygenated androgens (Figure 1), is of interest based on their intrinsic capacity to activate the AR.¹⁴ This pathway involves the conversion of the abundant adrenal precursor 11β-OH-androstenedione (11OHA4) into the highly potent AR ligand 11-ketotestosterone (11KT) in a molar range similar to that of T and dihydrotestosterone (DHT).^15,16 Compared with T and DHT, 11KT remains active longer, implying greater potential for AR activation whereas 11OHA4 has negligible androgenic potential, similar to that of DHEA.¹⁵ The clinical relevance of these 11-oxygenated androgens to patient outcomes was recently demonstrated in localized PCa.¹⁷ In that study, preoperative levels of the androgen 11KT was associated with metastasis-free survival, indicating that this hormone could potentially play a role in disease progression before the initiation of pharmacological therapies.¹⁷ Because of their adrenal source,¹⁸ it is anticipated that the influence of 11-oxygenated androgens on disease progression would be particularly accentuated in patients who have undergone castration and have reduced T levels due to ADT. A recent study evaluated the influence of 11-oxygenated androgens on outcomes of metastatic patients with CRPC who were initiating a new course of systemic therapy such as with enzalutamide, apalutamide, or mostly treated by conventional chemotherapy.¹⁹ Despite the limited sample size of 29 patients, the authors showed that elevated levels of 11KT were associated with longer progression-free survival in univariable analysis.¹⁹ Thus, limited data are emerging for CRPC, and no data are available for the castration-sensitive disease stage.

Figure 1.

Steroidome assessment of 145 patients with nonmetastatic prostate cancer of the PROCURE cohort with testosterone (T) levels below the commonly used criterion for castration of 1.7 nmol/L equivalent to 0.5 ng/mL or 50 ng/dL. A, Schematic representation of 11-oxygenated (11-OH; green) and canonical (black) steroids quantified by mass spectrometry. B, Flow diagram of the cohort study. Potent androgens are shaded in gray, and potent androgens found in the circulation of patients are shown in boldface type. Steroids that were not assessed are shown in italics. 11KA4 indicates 11-ketoandrostenedione; 11KAST, 11-ketoandrosterone; 11KT, 11-ketotestosterone; 11OHA4, 11β-hydroxyandrostenedione; 11OHAST, 11β-hydroxyandrosterone; 11OHT, 11β-hydroxytestosterone; A4, androstenedione; A5diol, androstenediol; ADT, androgen deprivation therapy; AST, androsterone; CRPC, castration-resistant prostate cancer; DHEA, dehydroepiandrosterone; DHEA-S, DHEA-sulfate; DHT, dihydrotestosterone; E₁, estrone, E₁-S, estrone-sulfate; E₂, estradiol.

We postulated that elevated levels of circulating 11-oxygenated androgens might expedite the onset of castration resistance in men undergoing ADT for recurrent nonmetastatic PCa following radical prostatectomy. We conducted a study with a group of 145 individuals from the prospective PROCURE cohort who had experienced PCa recurrence following prostatectomy and who subsequently received ADT and achieved castrated T. Our primary objective was to examine the effect of ADT on the levels of circulating 11-oxygenated androgens using a validated mass spectrometry (MS) assay (Figure 1, A) and establish their relationship to the development of castration resistance (CRPC). As a secondary objective, we explored the relationship between T and other steroids and CRPC occurrence.

PATIENTS AND METHODS

Study Cohort

PROCURE is a prospective, multicenter cohort comprising patients diagnosed with localized PCa who underwent radical prostatectomy, recruited between 2007 and 2012 at 4 Canadian university hospital centers.²⁰ Patients underwent regular clinical assessments, including monitoring PSA level at 3-month intervals for a period of 2 years and serial blood sampling. Then, the monitoring schedule was adjusted to intervals of 6 to 12 months or as determined at the discretion of the attending physicians.²⁰ PSA level at diagnosis, pathologic Gleason stage, pathologic T stage, nodal and margin status, disease progression, age, and BMI were available. Biochemical recurrence (BCR) was defined as the occurrence of a first PSA of > 0.2 ng/mL at any time after surgery or a detectable PSA of < 0.2 ng/mL with initiation of treatment radiotherapy or ADT.^17,21 The 145 nonmetastatic BCR patients for this analysis were from the pool of 456 with available plasma specimens during ADT and with castrated T (<0.5 ng/mL [1.7 nmol/L or 50 ng/dL]; Figure 1, B; Supplementary Table 1, https://www.jurology.com). The median duration between the initiation of ADT and blood collection was 7 months (4-10 months). For 50 patients, samples collected at the time of surgery were available.⁸ CRPC calculated for all patients starting from the day of BCR, was defined as disease progression (biochemical and/or radiographic), despite castrate serum T < 1.7 nmol/L, defined as a detectable and rising PSA > 1 ng/mL while radiographic progression outlined as the presence of lesions identified through radiographic assessment.

Study Approval

Patient provided written informed consent, and the protocol was approved by the CHU de Québec—Université Laval (Québec, Canada) Ethical Research Committee (#2012-362).

Quantification of Steroids

Seven unconjugated 11-oxygenated androgens were quantified (200 µL plasma) using chromatography–tandem MS (Figure 1, A).²² Deuterated steroids were employed as internal standards, and each run included quality controls. The coefficient of variation for each metabolite was consistently < 10%, ensuring accuracy and precision. Canonical steroids were also quantified by MS (Figure 1, A).²¹ Previous studies showed that sex steroids measured by MS display excellent reproducibility when stored for over 10 years at −80 °C.^23,24

Statistical Analyses

Patient characteristics were summarized using the median and IQR for continuous variables and frequency and proportion for categorical variables. Steroid levels underwent a log transformation to improve the normality of their distribution. The Wilcoxon-Mann-Whitney test or Kruskal-Wallis test, as appropriate, were used to compare the distribution of steroid levels by baseline clinical variables and to assess differences in steroid levels. Spearman correlation coefficients were used to evaluate associations between steroids and continuous clinical factors and to assess correlations among steroids. Kaplan-Meier survival curves were employed to estimate the survival of patients, as stratified by steroids categorized by median levels. Univariable and multivariable Cox proportional hazards models were used to estimate the CRPC HR. The multivariable models were adjusted for age, PSA level (continuous), pathological Gleason score, pathologic T stage, nodal status, margin status, and radiation therapy. The multivariable models were also conducted using steroids as a continuous variable. The functional form of the log-transformed steroids, as well as the nontransformed continuous variables (age and PSA), was assessed using the Supremum Test for Functional Form, and all were found to be appropriate. The association between hormones and CRPC was further evaluated using multivariable Fine and Gray’s competing risk analysis, acknowledging that some subjects may die from causes unrelated to PCa. The proportional hazard assumption was checked by the Supremum test. Statistical analyses were performed using SAS (version 9.4) and GraphPad Prism (version 10.0.3), and a P value of less than .05 was deemed statistically significant.

RESULTS

Study Cohort Characteristics

Our study comprised 145 men undergoing ADT from the multicentric prospective PROCURE cohort (Figure 1, B; Table 1) and a subset of 50 patients with paired plasma samples before and after castration (Supplementary Tables 2 and 3, https://www.jurology.com). The median follow-up time was 99 months (76-114) after BCR to the occurrence of CRPC. Within this cohort of 145 patients, 31 developed CRPC; among them, 32 deaths of which 17 were thus far attributable to PCa.

Table 1.

Patient Baseline Characteristics (n = 145)

Characteristics	Data value
Age at diagnosis, median (IQR), y	63.0 (59.1-68.4)
PSA at diagnosis, ng/mL, No. (%)
≤10	82 (57)
>10-20	41 (28)
>20	19 (13)
Missing	3 (2)
Pathological Gleason score, No. (%)
<7	2 (1)
3+4	29 (20)
4+3	44 (30)
>7	67 (46)
Missing	3 (2)
Pathological tumor stage, No. (%)
<pT3a	27 (19)
pT3a	59 (41)
>pT3a	56 (39)
Missing	3 (2)
Nodal invasion, No. (%)
pN0/pNx	110 (76)
pN1	32 (22)
Missing	3 (2)
Margin status, No. (%)
Positive	78 (54)
Negative	62 (43)
Missing	5 (3)
Metastatic status, No. (%)
M0	145 (100)
M1	0 (0)

Abbreviations: pN, nodal status; pNx, nodal status unknown; pT, pathologic T stage.

Predominance of 11-Oxygenated Androgens in Castrated Patients

All 145 patients displayed castrated T levels (<1.7 nmol/L). The most abundant 11-oxygenated androgens were the precursor 11OHA4 followed by the potent 11KT (Table 2). Levels of circulating 11-oxygenated androgens and other steroids analyzed prior to and during ADT (Supplementary Tables 2 and 3, https://www.jurology.com), and their correlations are provided (Supplementary Figure 1, https://www.jurology.com). No correlation was observed between 11KT and T or DHT prior to therapy, whereas these potent androgens correlated to some degree under ADT (r values of 0.68 and 0.49, respectively; P < .001). Notably, ADT resulted in a significant reduction in the levels of all circulating steroids except for 11-oxygenated androgens, which remained unaffected (Figure 2). By contrast, T was repressed by 98% with an average concentration of 3.14 ng/mL for untreated patients and decreasing to 0.08 ng/mL (equivalent to 0.28 nmol/L) under ADT (Figure 2, B). 11KT accounted for > 70% of all circulating androgens in castrated men, followed by T and DHT, representing 23% and 4%, respectively (Figure 2, C). At the individual patient level, the cumulative levels of potent androgens or total androgen pool including T, DHT and 11KT, reached concentrations up to 0.8 ng/mL, which is well above the 0.5 ng/mL T threshold observed for patients who had undergone castration (Figure 2, D).

Table 2.

Levels of Steroids in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy

Steroids	Mean±SD	Range	% Detecteda
11OHA4 pg/mL	1605.40±930.58	111.00-6480.00	100
11KA4 pg/mL	269.23±116.49	12.80-733.00	100
11OHT pg/mL	118.10±75.34	5.00-421.00	100
11KT pg/mL	282.61±140.71	11.60-607.00	100
11KDHTb pg/mL		—	0
11OHAST pg/mL	60.64±35.71	5.00-308.00	99
11KAST pg/mL	7.60±7.71	5.00-65.80	19
DHEA ng/mL	1.23±0.85	0.05-4.46	99
DHEA-S μg/mL	0.24±0.20	0.04-1.51	87
A5diol pg/mL	150.82±110.87	25.00-544.84	79
A4 ng/mL	0.34±0.20	0.05-1.29	97
T pg/mL	80.77±56.67	15.00-374.30	92
DHT pg/mL	13.65±11.07	5.00-53.00	49
AST pg/mL	69.68±51.44	25.00-261.86	55
E1 pg/mL	16.02±10.14	2.50-85.88	99
E1-S ng/mL	0.71±0.49	0.04-2.43	96
E2 pg/mL	2.97±2.39	0.50-23.58	91
Progesterone ng/mL	0.03±0.02	0.025-0.11	15

Abbreviations: 11KA4, 11-ketoandrostenedione; 11KAST, 11-ketoandrosterone; 11KT, 11-ketotestosterone; 11OHA4, 11β-hydroxyandrostenedione; 11OHAST, 11β-hydroxyandrosterone; 11OHT, 11β-hydroxytestosterone; A4, androstenedione; A5diol, androstenediol; AST, androsterone; DHEA, dehydroepiandrosterone; DHEA-S, DHEA-sulfate; DHT, diyhydrotestosterone; E₁, estrone; E₁-S, estrone-sulfate; E₂, estradiol; T, testosterone.

^aAbove the limit of quantification.

^bAll patients had undetectable levels (<5 pg/mL) of 11KDHT, and therefore subsequent analyses omitted this analyte.

Figure 2.

Effect of androgen deprivation therapy (ADT) on steroid levels in 50 patients. A, Differences in circulating levels of steroids before and during ADT in paired samples. B, Significant reduction in circulating testosterone (T; Testo) levels but not 11-ketotestosterone (11KT), in patients undergoing ADT. C, Relative abundance of potent androgens and androgen receptor agonists, T, 11-ketotestosterone (DHT), and 11KT, during ADT. D, Contribution of potent androgens to the total circulating androgen pool for each patient on ADT with castrated T levels (below 0.5 ng/mL or 1.7 nmol/L). Data are presented as mean ± SD. ***P < .0001. 11KA4 indicates 11-ketoandrostenedione; 11KAST, 11-ketoandrosterone; 11OHA4, 11β-hydroxyandrostenedione; 11OHAST, 11β-hydroxyandrosterone; 11OHT, 11β-hydroxytestosterone; A4, androstenedione; A5diol, androstenediol; AST, androsterone; DHEA, dehydroepiandrosterone; DHEA-S, DHEA-sulfate; DHT, dihydrotestosterone; E₁, estrone; E₁-S, estrone-sulfate; E₂, estradiol.

No significant relationships were observed between 11-oxygenated androgens under ADT and PSA level at diagnosis, Gleason score, pathologic T stage and margin status, and with BMI and age (Supplementary Tables 4-10, https://www.jurology.com).

Circulating 11-Oxygenated Androgens and Progression to CRPC

Kaplan-Meier analysis revealed that 11KT levels above the median (≥273 pg/mL) were associated with a shorter time to CRPC compared with lower 11KT < 273 pg/mL (P = .03) and in multivariate analysis with an HR_adj of 2.17 (95% CI, 0.99 to 4.71; P = .05; Figure 3; Table 3). We also used a T threshold of 0.7 nmol/L (equivalent to 0.2 ng/mL or 20 ng/dL) as defined in the PR-7 trial, with 140 out of 145 patients below this deeper level of castration (Figure 3, B). No significant association was observed for the other measured 11-oxygenated androgens based on median levels. The comparison of patients with low vs high 11KT level yielded the following CRPC event-free rates: 92% vs 82% at 5 years, 87% vs 74% at 7 years, and 87% vs 61% at 10 years, respectively. The multivariable Cox analysis of 11KT as a continuous variable did not reach significance with HR_adj of 1.52 (0.78-2.97); P = .2. The results were comparable when considering competing risks of non-PCa deaths.

Figure 3.

Kaplan-Meier curves for time to castration-resistant prostate cancer (CRPC) for 11-ketotestosterone (11 KT) analyzed (A) in all 145 patients with testosterone (T) levels below the clinical castration threshold of 1.7 nmol/L (0.5 ng/mL or 50 ng/dL) and the subset of 140 patients (B) with T levels below the castration threshold of 0.7 nmol/L (0.2 ng/mL or 20 ng/dL), starting from the day of biochemical recurrence. Patients were stratified by median 11KT levels.

Table 3.

Relationship Between Potent Androgen Levels and Time to Castration-Resistant Prostate Cancer

	Time to CRPC
pg/mL	nmol/L	No.	HR	95% CI	HRadj	95% CI	P value
Testosterone
Median
<70	<0.24	74	1		1
≥70	≥0.24	71	1.96	0.94-4.09	1.83	0.83-4.05	.14
Continuous
					1.99	1.08-3.68	.03
11KT
Median
<273	<0.90	73	1
≥273	≥0.90	72	2.31	1.09-4.90	2.17	0.99-4.71	.05
Continuous
					1.52	0.78-2.97	.22
DHT
Median
<5a	<0.02	74	1		1
≥5	≥0.02	71	2.41	1.14-5.13	2.39	1.09-5.27	.03
Continuous
					1.33	0.84-2.10	.23
Total androgenic pool (11KT + T + DHT)
Median
<356	<1.16	73	1		1
≥356	≥1.16	72	2.32	1.09-4.93	2.19	0.99-4.83	.05
Continuous
					2.11	0.97-4.62	.06

Abbreviations: 11KT, 11-ketotestosterone; CRPC, castration-resistant prostate cancer; DHT, dihydrotestosterone;  T, testosterone.

All patients were castrated with T levels below the commonly used criterion for castration of 1.7 nmol/L (equivalent to 0.5 ng/mL or 500 pg/mL or 50 ng/dL), and 97% of patients presented with T levels below 0.7 nmol/L (equivalent to 0.2 ng/mL or 200 pg/mL or 20 ng/dL). Kaplan-Meier survival curves were performed with steroids categorized by median levels, and the HR_adj were calculated on the basis of a Cox regression model, which was also applied with steroids as a continuous variable, as described in Patients and Methods.

^aCorresponds to the limit of quantification for this analyte.

Building on prior data from the PR-7 trial supporting a prognostic significance of other steroids,⁸ we observed that the androgen DHT, total androgen pool 11KT + T + DHT, DHEA, and estradiol (E₂) were linked to a shorter time to CRPC based on median levels (Supplementary Figure 2, https://www.jurology.com).

T level was not associated with time to CRPC based on the previous cutoff of lower levels of T (0.7 nmol/L; P = .3) or based on the median T level measured for our study population (0.24 nmol/L; P = .07; Figure 4; Table 3).⁷ When modeled as a continuous variable, T levels were significantly associated with a shorter time to CRPC with a HR_adj of 1.99 (1.08-3.68; P = .03; Table 3). A combined analysis of 11KT with T resulted in reclassification of the risk associated with the time to CRPC onset (Figure 4, B; Supplementary Figure 3, https://www.jurology.com).

Figure 4.

Kaplan-Meier curves for time to castration-resistant prostate cancer (CRPC) for median testosterone (T) of 70 pg/mL (equivalent to 0.24 nmol/L or 0.07 ng/mL; A), and the combined analysis of T and 11-ketotestosterone (11KT; B), starting from the day of biochemical recurrence and using lower values. Steroids are expressed as pg/mL.

For completeness, Kaplan-Meier survival curves for time to metastasis were provided (Supplementary Figure 4, https://www.jurology.com). As expected in this cohort, a rising PSA value under ADT heralding CRPC (median time of 57 months; IQR = 44-76), was more precise than the occurrence of metastasis (median time of 67 months; IQR = 48-80), which may not have all been detected in the absence of predefined scheduled imaging. Additional follow-up will be needed to capture all metastatic events (symptomatic and asymptomatic) and PCa deaths in this subcohort. Owing to the current limited number of deaths, no significant association with PCa-specific mortality was observed (data not shown).

DISCUSSION

Our results demonstrate that, for patients with recurrent nonmetastatic PCa under ADT, 11KT was the predominant androgen, comprising > 70% of circulating potent, tumorigenic androgens. A notable observation is that the levels of 11-oxygenated androgens including 11KT remained unaffected by castration, in contrast to the considerable decline observed for all other measured steroids.²⁵ Thus, despite achieving T levels characteristic of castrated patients, other potent bioactive androgens such as 11KT are present at substantial levels and thus may contribute to the activation of the AR, thereby promoting PCa progression. This conclusion is supported by our observation establishing a significant link between 11KT and a shorter time to progression to CRPC. Consequently, although the T level is effectively reduced by castration, the relatively large abundance of the potent 11KT increases the risk of transitioning to CRPC and emphasizes the increased importance of assessing 11KT levels. Owing to the size limitation, replication is warranted, and it was not possible to conduct an analysis with PCa-specific survival.

One study involving 29 metastatic CRPC patients has examined the clinical relevance of 11-oxygenated androgens in advanced PCa patients starting a new line of systemic therapy.¹⁹ This study found 11KT to be the most prevalent androgen,¹⁹ as presented herein, supporting that 11KT is the predominant active androgen in men undergoing ADT. However, the prognostic significance of 11KT appears to differ between castration-sensitive and castration-resistant forms of the disease, much like what has been observed for T level.²⁶ Here, steroids were measured during ADT for patients with recurrent castration-sensitive nonmetastatic PCa. Lower levels of nadir 11KT based on the median level of 273 pg/mL (0.90 nmol/L) were significantly linked to improved clinical outcomes, echoing findings from the PR-7 trial showing that lower T levels were associated with better outcomes.⁷ Conversely, for patients with advanced metastatic CRPC, higher 11KT, that is, > 115 pg/mL (0.38 nmol/L), measured before the start of therapy with an AR antagonist or chemotherapy in patients having undergone prior systemic treatments other than ADT, were linked to a more favorable response to subsequent therapy.¹⁹ This is consistent with earlier observations regarding T and adrenal precursors in prior studies of metastatic CRPC.^27,28 Thus, in both settings, the data support that elevated hormone levels play a role in driving disease progression. It is reasonable to consider that targeting the hormonal pathway with AR-pathway inhibitors could enhance clinical responses by mitigating the influence of these steroids on disease progression, such as with the use of abiraterone, which specifically targets CYP17 and leads to a reduction in 11KT level.²⁹ A recent randomized phase 3 trial, known as EMBARK, reported that for patients with high-risk BCR, both enzalutamide as a standalone treatment and enzalutamide in combination with ADT resulted in statistically significant and clinically meaningful improvements in metastasis-free survival compared with ADT alone.³⁰ Additional studies will be essential to replicate our initial findings and determine whether 11KT level can influence the duration of response to AR-pathway inhibitors, providing a more complete understanding of the relationship between 11-oxygenated androgens and treatment outcomes across various stages of PCa.

The strengths of this study are comprehensive pathological and clinical data, a median follow-up period of 99 months postrecurrence, and the quantification of seven 11-oxygenated androgens and many canonical steroids using a robust and validated MS assay. Our study was limited by the relatively small number of ADT-treated patients and CRPC events, notwithstanding the initial size of the PROCURE cohort. Still, having access to samples from patients undergoing prostatectomy has allowed us to collect clinical data on 11KT in real-time settings and evaluate its role in disease progression among individuals experiencing recurrent nonmetastatic disease. This task would have taken a minimum of a decade to accomplish if patient recruitment had been required. It is possible that other disease-relevant steroids may have been overlooked because of the sample size. We refrained from applying corrections for multiple testing because the study primarily focused on a restricted set of comparisons, considering the interconnected nature of 11-oxygenated androgens within the same pathway. The fact that we were able to confirm the prognostic significance of T, E₂, and DHEA, as previously observed,^7,8 strengthens the validity of our findings.

CONCLUSIONS

11KT stands out as the predominant circulating androgen in men undergoing ADT, and its higher levels are linked to more rapid progression to lethal castration resistance in men with recurrent, nonmetastatic PCa. Additional investigations are warranted to provide a more comprehensive understanding of the role of these circulating 11-oxygenated androgens in disease progression among patients who have undergone castration. Gaining a more precise understanding of how these hormones contribute to the transition to CRPC may help optimize hormone-treatment strategies for patients with castration-sensitive or -resistant PCa. This, in turn, could lead to tailored treatment strategies based on a simple blood-based prognostic and predictive hormonal biomarker(s), ultimately enhancing the survival of patients at high risk of having progressive disease.

Supplementary Material

juro-213-283-s001.pdf ^{(1.1MB, pdf)}