Late LHRH Agonists Injections Cause Spike in Testosterone Levels in Prostate Cancer

E. David Crawford, MD

Luteinizing hormone-releasing hormone (LHHR) agonists were found to often be administered later than the scheduled dosing used in patients with prostate cancer on pivotal clinical trials, leading to late testosterone values being greater than 20 ng/dL and the mean testosterone level almost doubling castration levels, according to results of a retrospective analysis published in the Journal of Urology.¹

In the analysis, investigators examined records of 22,860 patients with prostate cancer who were treated with LHRH agonists. Of the 85,030 injections administered, 84% were late for the 28-day month analysis and 27% experienced late dosing in the extended month analyses, respectively. During the 28-day month period, 60% of injections were late by more than 1 week and 29% were late by more than 2 weeks.

Testosterone values were calculated and 4% were dosed at more than 50 ng/dL for early/on time injections, while 15% of patients during the 28-day month period and 27% during the extended month period were greater than 50 ng/dL when late. When comparing early/on-time dosing to late injections, 22% versus 31% of testosterone values were greater than 20 ng/dL for the 28-day month and 21% versus 43% for the extended month. The mean testosterone was higher when late, with patients receiving 49 ng/dL for 28-day month and 79 ng/dL for extended month compared with those who received treatment early/on time (both 21 ng/dL). Of the administered injections, prostate-specific antigen (PSA) measurements were performed in 83% of patients, while testosterone assessments were conducted in 13% of patients.

“These new real-world findings confirm that late injection of LHRH agonists is common in clinical practice along with infrequent measurement of levels of testosterone,” lead study author, E. David Crawford, MD, stated in a press release.² “This is concerning as men with advanced prostate cancer not receiving their [androgen deprivation therapy (ADT)] on time may experience inadequate testosterone suppression, which could adversely impact disease progression and survival. Our analysis underscores the importance of administering LHRH injections in a timely fashion and conducting more frequent testosterone testing to ensure target levels below 20 ng/dL are achieved to reach the levels achieved with surgical castration.”

Between January 2007 and June 2016, retrospective analyses were conducted using 2 definitions of month. The study included a 28-day month (late dosing after days 28, 84, 112, or 168), as well as an extended month (late after days 32, 97, 128, or 194) where patients were given 1-, 3-, 4-, and 6-month doses, respectively. Patients received at least 2 injections of leuprolide acetate or triptorelin and had at least 1 measurement of PSA or testosterone levels.

The mean age was 73 to 75 years, with 73% to 78% of patients being Caucasian, 10% to 15% being African American, 1% to 3% were Asian, and 9% to 13% were unspecified. Despite being unable to identify patients on intermittent ADT, less than 4% of injections were administered more than 6 months late.

Investigators observed similarities in frequency of administration across the formulations. The frequency of the 1-month formulation was 60% for PSA and 12% for testosterone. Meanwhile, approximately 86% for PSA and 15% for testosterone were frequently given for the 3-month formulation mark, 84% and 11% for the 4-month mark, and 89% and 14% for the 6-month mark, respectively.

If dosing was late by longer than 2 weeks, investigators found that there was a negative impact on testosterone suppression. Incidences of late dosing were reported in 26% of situations where administered testosterone was dosed at more than 50 ng/dL and 41% where testosterone was greater than 20 ng/dL for the 28-day month. For the extended month definition, the incidences occurred at 35% for 50 ng/dL and 50% 20 ng/dL, respectively.

Additionally, higher mean testosterone level correlated with late injections. For the 28-day month, early/on-time injections caused a mean SD testosterone level of 21 ± 56 ng/dL, while late injections resulted in a mean testosterone level of 49 ± 107 ng/dL. For injections that were more than 2 weeks late, the mean testosterone level was 74 ± 131 ng/dL. For those who received extended month injections, the mean testosterone level increased from 21 ± 59 ng/dL when early/on time to 79 ± 135 ng/dl when late. The mean testosterone level was additionally observed as increasing to 98 ± 147 ng/dl for injections that were over 2 weeks late. For each definition, the proportion of testosterone higher than 50 ng/dL and higher than 20 ng/dL, in addition to the mean testosterone, showed significant differences between early/on-time and late injections (each P <.01) with consistent trends across all 4 formulations.

“These data underscore how important it is for Advanced Prostate Cancer Care (APCC) pathways to include mechanisms that ensure patients receive their LHRH injections on time and that treatment effects are monitored with both testosterone and PSA tests,” study author Jason M. Hafron, MD, partner at the Michigan Institute of Urology, stated in the press release. “In the current environment of restrictions in the number of patient visits due to the COVID-19 pandemic, these data are particularly relevant. It should also be recognized that use of the longest acting doses of LHRH agonists, such as 6-month, would reduce the potential for delays in dosing.”

References:

1. Crawford ED, Twardowski PW, Concepcion RS, et al. The impact of late luteinizing hormone-releasing hormone agonist dosing on testosterone suppression in patients with prostate cancer: an analysis of United States clinical data. J Urol. 2020;203(4):743-750. doi:10.1097/JU.000000000000057
2. Real-world data analysis published in the journal of urology explores frequency of late luteinizing hormone-releasing hormone agonist (LHRH) dosing and impact on testosterone suppression in patients with prostate cancer. News release. Business Wire; May 18, 2020. https://bwnews.pr/2FrdDqk.