Testosterone Therapy in Men with Localized Prostate Cancer

Educational Objectives

The goal of this program is to improve management of patients with prostate cancer through the use of testosterone therapy (TTh). After hearing and assimilating this program, the clinician will be better able to:

1. Relate testosterone levels to the risk for aggressive prostate cancer.
2. Select patients for testosterone replacement therapy.

Summary

Testosterone therapy (TTh) for men with localized prostate cancer: a systematic review by Kim et al (2021) found 15 studies investigating TTh after radical prostatectomy, 6 studies investigating TTh during active surveillance, and 9 studies investigating TTh after radiation therapy; none of the studies were randomized placebo-controlled trials (RCTs); TTh was once considered dangerous for men with prostate cancer; TTh is now considered to be potentially protective or therapeutic for men with prostate cancer

TT and radical prostatectomy: retrospective studies by Kaufman and Graydon (2004), Agarwal and Oefelein (2005), and Khera et al (2009) did not find a significant increase in biochemical recurrence in men who received TTh after radical prostatectomy; the participants in each study had low-grade, low-risk cancer; Pastuszak et al (2013) studied TTh after radical prostatectomy in men with high-grade, high-risk prostate cancer; the treatment group was compared with a eugonadal control group; high-risk prostate cancer was defined as a Gleason score of ≥8, positive surgical margins, and positive lymph nodes; patients at low and intermediate risk also were included; the rate of biochemical recurrence was 15% for patients receiving TTh and 53% for patients not receiving TTh; the results suggest that TTh may be protective against prostate cancer; an in vitro study by Song and Khera (2014) found that growth of prostate cancer cells is inhibited by removing testosterone; conversely, providing testosterone to cancer cells initially encourages growth; however, increasing the dose of testosterone suppresses growth of cancer cells; high and low ranges of testosterone may be protective (an “inverted U” relationship); the risk for growth of cancer cells may be highest in the hypogonadal range

Testosterone therapy and tumor incidence: Song et al (2017) injected LNCaP (ie, prostate cancer) cells into mice; the incidence of tumors in mice after orchiectomy was 9%; the incidence of tumors in mice given low-dose TTh after orchiectomy was 48%; the incidence of tumors in mice given high-dose TTh after orchiectomy declined to 25%; low testosterone levels in men are associated with increased risk for prostate cancer; low testosterone is associated with positive tumor margins, high-grade tumors, tumor burden, and higher Gleason scores; low testosterone may increase the risk of developing prostate cancer and the risk for more aggressive disease

Studies assessing the protective role of TT: Loeb et al (2017) — found no association between TTh and overall prostate cancer risk; patients who received TTh had a lower risk of developing aggressive prostate cancer; Yassin et al (2017) — found the rate of positive prostate biopsies was lowest in hypogonadal men receiving TTh, in comparison with untreated hypogonadal men and eugonadal men; men receiving TTh had lower severity of prostate cancer in terms of staging and grading; Ahlering et al (2020) — reported the rate of recurrence of cancer after radical prostatectomy (with no evidence of remaining disease) was 7.2% in patients receiving TTh and 12.6% in patients not receiving TTh; patients receiving TTh were 54% less likely to experience recurrence; the authors concluded that TTh delays the time to recurrence by an average of 1.5 yr; Saad et al (2020) — followed hypogonadal men for 12 yr; the incidence of prostate cancer, major adverse cardiovascular events, and mortality were lower in men taking TTh compared with untreated men; the Food and Drug Administration (FDA) allowed administration of TTh after radical prostatectomy (for an Investigational New Drug application) in patients with two undetectable prostate specific antigen (PSA) results and Gleason scores ≤3+4 the TRAVERSE study: a upcoming RCT comparing men receiving TTh vs those receiving a placebo; the primary outcome is major adverse cardiac events; the study also includes assessment of the incidence of high-grade prostate cancer in men receiving TTh vs those receiving a placebo

TT and active surveillance: several studies have found no increase in progression of prostate cancer with TTh; Morgentaler et al (2011) — no cancer progression was found in 13 men taking TTh for a mean of 24 mo, and no cancer was identified in 54% of patients on follow-up biopsies; Kacker et al (2016) — studied men taking TTh for ≥6 mo; no progress of cancer was found in men with Gleason scores ≤3+3; progression was found in 3 men with Gleason ≥3+4; there was no increase in prostate cancer progression or increased tumor volume for men on active surveillance

TT after radiation therapy: Sarosdy (2007) found testosterone levels in men receiving TTh after brachytherapy increased from 188 ng/dL to 498 ng/dL; TTh was not stopped in any patients because of progression or recurrence of prostate cancer; studies by Morales et al (2009) and Pastuszak et al (2013) of hypogonadal men receiving TTh found no increase in PSA or prostate cancer recurrence over 14.5 mo and 30 mo, respectively; Pastuszak et al (2015) — 6 patients receiving TTh had a biochemical recurrence; 3 patients were being treated with androgen deprivation therapy; testosterone levels may have been normalizing, which may have been mistaken for biochemical recurrence

Prostate saturation model: PSA levels may increase until testosterone levels reach a saturation point; patients with presumed biochemical recurrence may be normalizing their testosterone levels; the model states that higher testosterone levels lead to greater PSA levels; administration of leuprolide (eg, Eligard, Lupron, Viadur) stops production of testosterone and decreases PSA levels to 0; increasing testosterone levels to a saturation point of ≈250 ng/dL may increase PSA levels; PSA levels may increase ≈0.3 ng/dL in a patient receiving TTh with a baseline testosterone level of 150 ng/dL; Khera et al (2011) reported that PSA levels and testosterone levels are correlated in patients with testosterone levels <250 ng/dL; increase in PSA levels were seen after 12 mo of TTh only in patients with baseline testosterone levels <250 ng/dL

TTh and prostate cancer: clinicians are becoming more comfortable prescribing TTh for patients who underwent radical prostatectomies; Millar et al (2016) found that 96% of Canadian urologists considered TTh as safe after radical prostatectomy; 84% considered TTh safe after radiation therapy; 86% considered TTh safe after brachytherapy; 65% considered TTh safe during active surveillance; guidelines from the American Urological Association state (as a strong recommendation) that clinicians should inform patients of the absence of evidence linking TTh to the development of prostate cancer; patients with testosterone deficiency and a history of prostate cancer should be informed there is inadequate evidence to quantify the risk-benefit ratio of TTh; Huggins (1965) proposed that both hormonal deprivation and hormonal excess may have therapeutic benefits

Readings

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; Davidson E, Morgentaler A. Testosterone therapy and prostate cancer. Urol Clin North Am. 2016;43(2):209-216. doi:10.1016/j.ucl.2016.01.007; 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; Kim M, Byun SS, Hong SK. Testosterone replacement therapy in men with untreated or treated prostate cancer: do we have enough evidence? World J Mens Health. 2021;39(4):705-723. doi:10.5534/wjmh.190158; Loeb S, Folkvaljon Y, Damber JE, et al. Testosterone replacement therapy and risk of favorable and aggressive prostate cancer. J Clin Oncol. 2017;35(13):1430-1436. doi:10.1200/JCO.2016.69.5304; Pastuszak AW, Khanna A, Badhiwala N, et al. Testosterone therapy after radiation therapy for low, intermediate and high risk prostate cancer. J Urol. 2015;194(5):1271-1276. doi:10.1016/j.juro.2015.05.084; Saad F, Caliber M, Doros G, et al. Long-term treatment with testosterone undecanoate injections in men with hypogonadism alleviates erectile dysfunction and reduces risk of major adverse cardiovascular events, prostate cancer, and mortality. Aging Male. 2020;23(1):81-92. doi:10.1080/13685538.2019.1575354; Song W, Khera M. Physiological normal levels of androgen inhibit proliferation of prostate cancer cells in vitro. Asian J Androl. 2014;16(6):864-868. doi:10.4103/1008-682X.129132; Yassin A, Salman M, Talib RA, et al. Is there a protective role of testosterone against high-grade prostate cancer? Incidence and severity of prostate cancer in 553 patients who underwent prostate biopsy: a prospective data register. Aging Male. 2017;20(2):125-133.

Disclosures

For this program, the following relevant financial relationships were disclosed and mitigated to ensure that no commercial bias has been inserted into this content: Dr. Khera has been a consultant for AbbVie, Clarus Therapeutics, Endo, Acerus, and Antares Pharma. Members of the planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Khera was recorded at the 4th Annual Meeting of the Androgen Society, held April 21-23, 2022, and presented by the Androgen Society in Orlando, FL. For more information on further CME activities from this presenter, please visit https://www.androgensociety.org. Audio Digest thanks the speakers for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0.75 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0.75 CE contact hours.

Lecture ID:

UR452001

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.