TRT in Patients With Prostate Cancer on Active Surveillance: Are We Really Putting Gas on Fire?

Exogenous testosterone has long been attributed to the development and progression of prostate cancer. In fact, androgen deprivation therapy (ADT) is the mainstay treatment for patients with advanced and metastatic prostate cancer. Nevertheless, the aging male population is at increased risk for both hypogonadism and prostate cancer. Therefore, some hypogonadal men with prostate cancer may be deprived of the benefits of testosterone replacement therapy (TRT) with significant effects on their quality of life, especially since many of these patients will be managed with active surveillance rather than treatment.^1,2

Abraham Morgentaler, MD, FACS, and Abdulmaged M. Traish, PhD, described the androgen saturation model where prostate growth is highly affected by androgens in the setting of very low concentrations but becomes less sensitive to higher or oscillating androgens levels. They described that androgens operate through activation of the androgen receptors, whose maximal binding capacity is reached at androgen concentration below normal physiological levels.³ Findings from multiple studies showed that TRT did not confer worse oncologic outcomes after prostate cancer treatment.^4-6 Interestingly, another study showed that TRT after prostatectomy might reduce or delay time to biochemical recurrence.⁷

There are limited data concerning the effect of TRT among patients with treatment-naive prostate cancer on surveillance. We hypothesized that testosterone replacement does not have a negative impact on the oncologic outcomes of these patients.

We performed a retrospective review of our institutional active surveillance prostate cancer database. Hypogonadal men with prostate cancer who received TRT during surveillance were identified. To limit the effect of confounders, we performed propensity score matching to identify a control group of patients who underwent surveillance without TRT (in terms of age, body mass index, Charlson Comorbidity Index, race, prostate volume, Gleason grade, number of positive cores, percent core involvement, clinical T stage, prostate specific antigen [PSA], PSA density [PSAd], PSA doubling time [PSADT], National Comprehensive Cancer Network [NCCN] risk status, family history of prostate cancer, and follow-up duration).⁸

Patients with NCCN very low, low, and favorable intermediate-risk disease were offered active surveillance and followed in accordance with NCCN Guidelines with PSA testing no more often than every 6 months unless clinically indicated and annual digital rectal examination no more often than every 12 months unless clinically indicated.⁹ Follow-up MRI and/or prostate biopsy were performed as clinically indicated. Prostate biopsies were graded based on the International Society of Urological Pathology consensus.¹⁰ Follow-up of patients receiving testosterone entailed repeat testosterone, hematocrit, and liver function tests at 6 to 12 weeks after treatment initiation, then at the time of PSA testing per active surveillance protocol described above.

Conversion to treatment was defined as discontinuation of surveillance with the receipt of radiotherapy, radical prostatectomy, or ADT. Twenty-four patients who received TRT during surveillance were identified and were matched to 72 patients on surveillance who did not receive TRT.⁸

Median duration of TRT was 5 years (IQR, 3-9), and median duration of TRT while on active surveillance was 3 years (range, 1-6). After a median follow-up of 6 years (IQR, 3-9), 22 patients (23%) converted to treatment. Patients who did not receive TRT had a mean increase in PSA of 0.08 ng/ml per month (P < .01) compared with only 0.01 ng/ml per month (P < .04) for those who received TRT.⁸

Five patients in the TRT group converted to treatment compared with 17 in the control group (P < .20). One patient died because of prostate cancer in the no-TRT group.

Three- and 5-year treatment-free survival rates were 95% and 74%, respectively, in the TRT group compared with 86% and 76%, respectively, in the no TRT group (log-rank P=.87).⁸ Multivariable Cox regression model showed that only PSA density was associated with conversion to treatment (HR, 1.08; 95% CI, 1.03-1.13; P = .001).

Our findings are in line with the androgen saturation model in that we did not identify a difference in conversion to treatment between both groups. However, controversy about safety of TRT in the context of prostate cancer among clinicians providing care to the hypogonadal patient remains. The European Association of Urology Guidelines still considers localized and metastatic prostate cancer an absolute contraindication for testosterone replacement.¹¹ The American Urological Association states there is no strong evidence linking testosterone replacement with increased risk of developing prostate cancer.¹²

Additionally, findings from a meta-analysis performed by Parizi et al showed that TRT does not increase the risk of biochemical recurrence after local therapy with curative intent.5 For active surveillance, evidence remains even more limited. The meta-analysis found a total of 6 studies, but only 1 was a double-armed study with shorter follow-ups compared with our study.^13,14 The other 5 studies in that meta-analysis were limited to case reports.^15-20 The influence of androgens on prostate cancer pathophysiology seems to be so heterogenous that its administration as a treatment alternative has also been explored. Isaacs et al laid out the rationale behind this concept by describing bipolar androgen therapy. The authors described that supraphysiologic levels of testosterone induce cell death in castration-resistant prostate cancer that is well known for displaying an upregulation of androgen receptors.²¹

Although the available evidence, including our retrospective study, does not support the notion that TRT may adversely affect outcomes for hypogonadal men with localized prostate cancer on active surveillance, close follow-up of these patients is recommended. Clinicians should ensure that there is a low threshold for obtaining prostate MRIs and repeat biopsies with discontinuation of TRT with any evidence of disease progression.

The retrospective nature of our analysis and propensity score matching have their inherent limitations. Additionally, the small sample size precludes further analysis of the effect of the individual routes of administration of TRT.

References

1. Society. AC. Cancer Statistics Center 2022 [Available from: http://cancerstatisticscenter.cancer.org2022.
2. Harman SM, Metter EJ, Tobin JD, et al. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab. 2001;86(2):724-731. doi:10.1210/jcem.86.2.7219
3. Morgentaler A, Traish AM. Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth. Eur Urol. 2009;55(2):310-320. doi:10.1016/j.eururo.2008.09.024
4. Kaplan AL, Trinh QD, Sun M, et al. Testosterone replacement therapy following the diagnosis of prostate cancer: outcomes and utilization trends. J Sex Med. 2014;11(4):1063-1070. doi:10.1111/jsm.12429
5. Parizi MK, Abufaraj M, Fajkovic H, et al. Oncological safety of testosterone replacement therapy in prostate cancer survivors after definitive local therapy: a systematic literature review and meta-analysis. Urol Oncol. 2019;37(10):637-646. doi:10.1016/j.urolonc.2019.06.007
6. Boyle P, Koechlin A, Bota M, et al. Endogenous and exogenous testosterone and the risk of prostate cancer and increased prostate-specific antigen (PSA) level: a meta-analysis. BJU Int. 2016;118(5):731-741. doi:10.1111/bju.13417
7. Ahlering TE, My Huynh L, Towe M, et al. Testosterone replacement therapy reduces biochemical recurrence after radical prostatectomy. BJU Int. 2020;126(1):91-96. doi:10.1111/bju.15042
8. Daza J, Ahmad A, Shabir U, et al. Does testosterone replacement therapy increase the risk of conversion to treatment in patients with prostate cancer on active surveillance? Urol Oncol. 2023;S1078-1439(23):00215-00216. doi:10.1016/j.urolonc.2023.06.002
9. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 4.2023. October 27, 2023. bit.ly/3ScFnCz
10. Epstein JI, Egevad L, Amin MB, et al. The 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma: definition of grading patterns and proposal for a new grading system. Am J Surg Pathol. 2016;40(2):244-252. doi:10.1097/PAS.0000000000000530
11. EAU Guidelines 2023. Accessed October 27, 2023. bit.ly/3MeF4Dd
12. Mulhall JP, Trost LW, Brannigan RE, et al. Evaluation and management of testosterone deficiency: AUA Guideline. J Urol. 2018;200(2):423-432. doi:10.1016/j.juro.2018.03.115
13. Kim M, Byun SS, Hong SK. Testosterone replacement therapy in men with untreated or treated prostate cancer: do we have enough evidences?. World J Mens Health. 2021;39(4):705-723. doi:10.5534/wjmh.190158
14. Kacker R, Hult M, San Francisco IF, et al. Can testosterone therapy be offered to men on active surveillance for prostate cancer? preliminary results. Asian J Androl. 2016;18(1):16-20. doi:10.4103/1008-682X.160270
15. Morgentaler A. Two years of testosterone therapy associated with decline in prostate-specific antigen in a man with untreated prostate cancer. J Sex Med. 2009;6(2):574-577. doi:10.1111/j.1743-6109.2008.01066.x
16. Morgentaler A, Lipshultz LI, Bennett R, et al. Testosterone therapy in men with untreated prostate cancer. J Urol. 2011;185(4):1256-1260. doi:10.1016/j.juro.2010.11.084
17. Berookhim B, Krishnan R, Nelson C, Mulhall J, editors. Testosterone replacement therapy in men undergoing active surveillance for prostate cancer. JOURNAL OF SEXUAL MEDICINE; 2015: WILEY-BLACKWELL
18. Ory J, Flannigan R, Lundeen C, et al. Testosterone therapy in patients with treated and untreated prostate cancer: impact on oncologic outcomes. J Urol. 2016;196(4):1082-1089. doi:10.1016/j.juro.2016.04.069
19. Morgentaler A, Magauran D, Neel D, et al. Recurrence rates following testosterone therapy in a large clinical cohort of men with prostate cancer. J Urol. 2018;199(4S):e206. doi:10.1016/j.juro.2018.02.558
20. Morales A. Effect of testosterone administration to men with prostate cancer is unpredictable: a word of caution and suggestions for a registry. BJU Int. 2011;107(9):1369-1373. doi:10.1111/j.1464-410X.2011.10193.x
21. Isaacs JT, D'Antonio JM, Chen S, et al. Adaptive auto-regulation of androgen receptor provides a paradigm shifting rationale for bipolar androgen therapy (BAT) for castrate resistant human prostate cancer. Prostate. 2012;72(14):1491-1505. doi:10.1002/pros.22504