Serum testosterone level predicts the effective time of androgen deprivation therapy in metastatic prostate cancer patients

Abstract

Androgen deprivation therapy (ADT) is the standard of care for patients with metastatic prostate cancer. However, whether serum testosterone levels, using a cut-off point of 50 ng dl−1, are related to the effective time of ADT in newly diagnosed prostate cancer patients remains controversial. Moreover, recent studies have shown that some patients may benefit from the addition of upfront docetaxel chemotherapy. To date, no studies have been able to distinguish patients who will benefit from the combination of ADT and docetaxel chemotherapy. This study included 206 patients who were diagnosed with metastatic prostate cancer and showed progression to castrate-resistance prostate cancer (CRPC). Serum testosterone levels were measured prospectively after ADT for 1, 3, and 6 months. The endpoint was the time to CRPC. In univariate and multivariate analyses, testosterone levels <50 ng dl−1 were not associated with the effective time of ADT. Receiver operating characteristic and univariate analysis showed that testosterone levels of ≤25 ng dl−1 after the first month of ADT offered the best overall sensitivity and specificity for prediction of a longer time to CRPC (adjusted hazard ratio [HR], 1.46; 95% confidence interval [95% CI], 1.08–1.96; P = 0.013). Our results show that serum testosterone level of 25 ng dl−1 plays a prognostic role in prostate cancer patients receiving ADT. A testosterone value of 25 ng dl−1 after the first month of ADT can distinguish patients who benefit from ADT effectiveness for only a short time. These patients may need to receive ADT and concurrent docetaxel chemotherapy.

Maximal testosterone suppression in the management of recurrent and metastatic prostate cancer

“…Five prospective trials demonstrated that patients achieving serum testosterone levels ≤0.7, ≤0.9, ≤1.0, or ≤1.1 nmol/l, were associated with longer time to CRPC and/or death compared with those having higher testosterone levels, respectively. [21][22][23]27,29 Four of six retrospective studies of localized, locally advanced, or metastatic PCa also demonstrated improved outcomes (lower rates of testosterone breakthrough, PFS, CSS, or OS) for patients achieving testosterone suppression ≤0.7 nmol/l or ≤1.1 nmol/l compared to those with serum testosterone levels >0.7 nmol/l or >1.1 nmol/l, respectively. 26,28,30,31 A similar trend was seen in a recent post-hoc analysis of the ICELAND study, which demonstrated an association between lower nadir testosterone level and a trend toward longer time to PSA (CRPC) progression (≤0.7 nmol/l vs. >0.7 nmol/l to ≤1.7 nmol/l; HR 5.06; 95% CI 1.3-16.1; p=0.062; at the time of publication, the ICELAND study report was only available in abstract form).…”

“…27 In the next largest trial, 206 patients with metastatic PCa received either monthly LHRHA or a three-month depot along with an AR antagonist (bicalutamide or flutamide following bicalutamide withdrawal). 29 Patients with testosterone levels ≤0.9 nmol/l one month after initiating ADT experienced a longer time to CRPC (mean 19.1 months) compared with those with testosterone levels >0.9 nmol/l (mean 14.6 months; p=0.0004). Patients with testosterone levels ≤0.7 nmol/l six months after initiating ADT also had a longer time to CRPC (adjusted hazard ratio [HR] 1.99; 95% …”

“…21,26,27 An additional trial demonstrated a significantly lower risk of death with mean six-month testosterone level of 1.4 nmol/l vs. higher levels (p<0.05), 28 while two prospective trials each demonstrated improvements in time to CRPC with testosterone levels ≤0.9 and ≤0.7 nmol/l compared with higher levels (p=0.0004 and p=0.015, respectively). 27,29 Finally, a retrospective analysis showed no OS or CSS benefits for testosterone level <0.7 nmol/l compared with ≥0.7 nmol/l (p=0.17 and p=0.29, respectively). 25 Although prospective studies are necessary to assess whether adjusting therapy to achieve a lower level of testosterone will result in improved outcomes, observational studies suggest that lowering the target threshold of testosterone to ≤0.7 nmol/l was most closely associated with improved survival-related outcomes and a prudent goal for therapy (Fig.…”

“…Among the 11 trials reviewed, nine reported survival-related outcomes for patients with testosterone levels ranging from ≤0.1 nmol/l to <1.1 nmol/l, 21,22,24,[26][27][28][29][30] eight of which showed significant improvements in these outcomes. A single retrospective study observed a significant improvement in OS with testosterone levels of ≤0.1 nmol/l compared with levels >0.1 nmol/l; p=0.014) 24 and two studies, one prospective 22 and one retrospective, 30 showed significant improvements in PFS-related outcomes (time to CRPC, p=0.05 and survival free of androgen-independent progression, p<0.03, respectively) at testosterone levels <1.1 nmol/l compared with >1.1 nmol/l.…”

“…[21][22][23]27,29 The largest prospective analysis included data from 626 patients, with localized or locally advanced PCa, either undergoing orchiectomy or receiving LHRH agonist (LHRHA) therapy plus a non-steroidal antiandrogen for a minimum of four weeks. 27 Serum testosterone levels were assayed every two months and a relationship between testosterone level and time to CRPC was observed.…”