Dr. Siemens started by making the argument that lower testosterone levels are better. The PR-7 study randomly assigned patients experiencing biochemical failure after radiation therapy or surgery to continuous vs intermittent ADT. A secondary analysis of this trial assessed the relationship between testosterone levels in the first year of therapy and the cancer-specific survival (CSS) and time to CRPC among men in the continuous ADT arm . There was a significant difference in CSS (p=0.015) and time to CRPC (p=0.02) among men who had first year testosterone nadir ≤0.7, >0.7 to ≤1.7, and ≥1.7 nmol/L. Furthermore, patients with nadir >0.7 nmol/L had a higher risk of cancer-specific mortality (vs 0.7-1.7 nmol/L HR 2.08; 95%CI 1.28-3.38). Subsequently, in a cohort of 225 Japanese men who underwent combined androgen blockade as first line therapy, no variable was associated with PFS. However, on multivariable analysis, testosterone <20 ng/dL was a significant prognostic factor for PFS (p=0.005). The authors concluded that the critical factor for prognosis was not a rapid decrease but whether nadir testosterone level achieved <20 ng/dL.
Dr. Siemens notes that there are a number of reasons why studies may not show an effect of low testosterone. These include more effective testosterone suppression with certain drugs, and that in adjuvant radiation ADT is a radiosensitizer and may have different biological effects compared to long term suppression of disease recurrence. Testosterone levels matter because (i) the androgen receptor is the undisputed accelerator of prostate cancer, (ii) testosterone stimulation of the androgen receptor increases genomic instability and oncogenic alterations, and (iii) testosterone plays a role in pro-metastatic signaling and not just proliferation.
Dr. Siemens then notes, “what about intermittent therapy where the testosterone rises off treatment”? The key concept is to achieve a testosterone as low as possible during the treatment interval and not necessarily life-long therapy. The mechanism is to hit cancer cells hard and then stop treatment allowing for repopulation with a more favorable androgen sensitive phenotype. Dr. Siemens concluded by making several points: (i) multiple studies indicate the importance of achieving low testosterone during ADT, (ii) allowing testosterone recovery during off treatment interval is not inconsistent with this observation, (iii) when monitoring testosterone, switching drugs if testosterone is warranted if the testosterone is >0.7 nmol/mL.
Dr. Nabid then provided a rebuttal, making the argument that testosterone nadir levels don’t necessarily matter. Dr. Nabid notes that there are two randomized trials that have assessed this question in the intermediate and high-risk prostate cancer setting. In PCS III, 600 patients with intermediate risk prostate cancer were randomized to hormonal therapy with 70 Gy vs 76 Gy radiotherapy. A second study, PSC IV randomized 630 high risk prostate cancer patients to either 36 months androgen blockade + radiotherapy vs 18 months androgen blockade + radiotherapy. For the intermediate risk patients, over 8.1 years of following, there was a non-significant risk of biochemical failure, prostate cancer progression, and resistance to castration. Over a median 9.4 years of follow-up for the high-risk study, similarly there was also no differences in outcomes for high risk patients with regards to biochemical failure rates prostate cancer progression and resistance to castration.
In conclusion, Dr. Nabid makes a number of summary points for localized prostate cancer treated with radiotherapy and ADT, (i) at the end of ADT, 91.1% of patients achieved castration levels of testosterone regardless of ADT duration, (ii) the outcomes were not different between patients with testosterone levels ≤0.7 nmol/L and between >0.7 and <1.7 nmol/L, (iii) we should have caution for patients with testosterone levels ≥1.7 nmol/L, and (iv) a testosterone level ≤0.7 nmol/L at the end of ADT did not predict better outcomes.
Presented By: Robert Siemens, MD, Queen’s University, Kingston, ON, Canada; Abdenour Nabid, MD, Centre Hospitalier de Universitaire de Sherbrooke, Sherbrooke, QC, Canada
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre Twitter: @zklaassen_md at the 72nd Canadian Urological Association Annual Meeting - June 24 - 27, 2017 - Toronto, Ontario, Canada
1. Klotz L, O’Callaghan C, Ding K, et al. Nadir testosterone within first year of androgen-deprivation thereapy (ADT) predicts for time to castration-resistant progression: a secondary analysis of the PR-7 trial of intermittent versus continuous ADT. J Clin Oncol 2015;33(10):1151-1156.