Prospective study of endogenous testosterone recovery following neoadjuvant hormonal blockade and radical prostatectomy in high-risk prostate cancer patients.

Background: Recovery of endogenous testosterone following androgen deprivation therapy (ADT) for prostate cancer is uncertain.

Aim: To prospectively evaluate testosterone (T) recovery rates and timing after neoadjuvant ADT followed by radical prostatectomy (RP).

Methods: We report a secondary analysis from a phase II randomized trial involving 64 patients who received a 3-month neoadjuvant ADT regimen (goserelin, abiraterone with prednisone and for half of the participants, apalutamide) followed by RP. Total Testosterone (TT) was measured at baseline, during ADT (3 m), and after 4, 8, and 12 months post-ADT cessation. Return to non-castrate levels (TT > 50 ng/dL), to normal (TT ≥ 300 ng/dL), and back to baseline level (BTB, defined as TT ≥ baseline) are reported. Predictive factors were analyzed using uni and multivariate analyses (MVA), and quality of life (QoL) was assessed with the validated Expanded Prostate Cancer Index Composite (EPIC-50).

Outcomes: Chance and chronology of T recovery 1 year after ADT cessation.

Results: Median T levels were as follows: baseline 442 ng/dL (IQR: 321-505); 4 months post-ADT, 144 ng/dL (IQR: 35-284); 8 months, 316 ng/dL (IQR: 243-438); and 12 months, 358 ng/dL (IQR: 285-477). By 12 months, 98.1% of patients reached non-castrate levels, 79.5% returned to normal, and 33.9% to BTB. Half of the patients achieved T > 50 ng/dL in 5 months, T ≥ 300 ng/dL in 9.1 months, and BTB in 13.1 months. In MVA, baseline T was the only significant predictor for T normalization (OR: 1.015; P < .01), while age and baseline T were predictors for BTB recovery (OR for age: 0.88; P = .02; OR for baseline T: 0.99; P = .02). QoL assessment showed persistently low sexual function, with minor improvements over time (median scores: 0 [0-5.6] at 4 months and 2.8 [0-29.2] at 12 months, P < .01), while sexual bother starts very low but significantly increases during follow up (median scores: 100 [IQR: 42.2-100] at 4 months to 50 [IQR: 0-100] at 12 months, P = .03).

Clinical implications: Long-term lower T levels can occur even after short-term ADT, persisting longer than anticipated. Clinicians should consider this in patient management.

Strengths and limitations: Our strengths include the prospective, controlled design and a rarely reported ADT triple therapy followed by RP. Limitations include the use of immunoassay to measure TT.

Conclusion: After 3 months of neoadjuvant triple ADT and RP, significant recovery to non-castrate and normal T levels is seen in most patients by 1 year; yet, BTB recovery is achieved in only a third. Higher baseline T and younger age predict faster T normalization and BTB recovery, respectively.