New paper below from Dr. Morgentaler (Published Online:21 Jul 2021) [1].
Note that some of the men were put on a modified BAT (bipolar androgen therapy) protocol,
Introduction:
Although prostate cancer (PCa) has long been considered an absolute contraindication for testosterone therapy (TTh), growing literature suggests TTh may be safely offered to men with localized PCa. We here present a single-center series of men treated with TTh for relief of symptoms, despite having more advanced disease, namely biochemical recurrence (BCR) or metastatic PCa (MET).
Methods:
We identified men treated with TTh with BCR, MET, or adjuvant androgen deprivation therapy (ADT). Consent included risks of rapid PCa progression and death. Laboratory and clinical results were analyzed.
Results:
Twenty-two men received TTh: 7 with BCR, 13 with MET, and 2 with adjuvant ADT. Median age was 70.5 years (range 58–94). Median TTh duration was 12 months (range 2–84) overall, including 20 months for BCR and 9.5 months for MET. Mean serum testosterone (T) increased from 210 to 1111 ng/dL. Median PSA (interquartile range) increased from 3.1 ng/mL (0.2–4.5) to 13.3 ng/mL (3.4–22) in the BCR group, 6.3 ng/mL (1.2–31) to 17.8 ng/mL (6.2–80.1) in the MET group, and <0.1 to 0.3 ng/mL in the ADT group. All patients reported symptom relief, especially improved vigor and well-being. Overall mortality was 13.6% and PCa-specific mortality was 4.5% during the period of TTh and 6 months after discontinuation. Seven of 10 with follow-up imaging within 12 months showed no progression. Five men have died: three during TTh and two succumbed at 2 years or longer after discontinuing TTh. One of the three deaths during TTh was PCa-specific. Three men developed significant bone pain at 7–41 months; two discontinued TTh and one continued, after focal radiation. There were no cases of rapid-onset complications, vertebral collapse, or pathological fracture.
Conclusions:
These initial observations indicate TTh was not associated with precipitous progression of PCa in men with BCR and MET, suggesting a possible role for TTh in selected men with advanced PCa whose desire for improved quality of life is paramount.
Discussion
To the best of our knowledge this is the first reported clinical series in the PSA era of outcomes with TTh specifically in men with BCR or MET in a clinical setting, and not part of a formal trial. A total of 20 men with nonlocalized PCa and two receiving ADT deemed at high risk for metastases received TTh for up to 7 years with a median duration of >1 year, with considerable subjective improvement in quality of life, and without rapid progression, morbidity, or death. There was only one PCa-specific death during TTh, occurring 11 months after initiation of TTh in a 94-year-old man with diffuse metastases and initial PSA 546 ng/dL. Although this series of cases cannot establish safety of TTh in the setting of advanced PCa, these results do challenge the long-standing assumption that even transient exposure to increased serum T in a man with advanced PCa-with testosterone flare, for example, will rapidly precipitate morbidity or death.15
The original basis for the belief that TTh is dangerous for PCa arose from the work of Huggins and Hodges, who in 1941 concluded that “Testosterone injections cause activation of prostate cancer1” Contemporary review of their original data revealed it was based on erratic acid phosphatase data for only 14 days in a single hormonally intact individual.16 Fowler and Whitmore reported 45 of 52 men who received TTh demonstrated an undefined “unfavorable result” within 30 days; however, all but four of these men had already undergone castration or were on estrogen treatment to suppress serum T.2 Of these four men, three demonstrated no unfavorable results despite daily injections of T propionate for 51, 55, and 310 days. The appearance of poor outcomes for men on ADT but not for men who were hormonally intact inspired the development of the saturation model, which demonstrates a finite capacity of androgens to stimulate PCa growth, with exquisite sensitivity to changes in androgen concentrations at low values, and then insensitivity once the saturation point is reached,9 which appears to be ∼250 ng/dL in men.17,18 This study provides suggestive evidence for saturation in nonlocalized PCa, since men with BCR failed to demonstrate precipitous increases in PSA despite substantial periods of TTh.
There is scant literature regarding testosterone administration in men with advanced PCa in the PSA era. Leibowitz et al. reported results of a variety of strategies involving TTh in a mixed population of 96 men with PCa, of which it appears 31 likely had metastatic disease.19 Clinical trials of BAT in men with castrate-resistant prostate cancer reported a PSA decline in 7 of 14 men, and evaluable disease was reduced in 5 of 10 men.12 To optimize the duration of time on TTh, mBAT was developed13 and was used in seven men in the MET group in this study.
There are several notable observations from this clinical series. First, there exists a set of men for whom quality of life is more important than duration of life. Each patient understood that their choice of TTh could cause immediate or hastened disease progression, morbidity, and death. Second, these men only continued TTh because it provided them with symptomatic benefits to a degree that made it worthwhile, in their estimation, to risk their lives. This defies a frequently made assertion that TTh provides only minimal symptomatic benefits.20 Nearly all men experienced increased vigor. Sexual desire and ability were improved in many, and several were able to resume sexual activity after years without it, especially those on ADT. One man gained enough strength to give up the need for a walker. Several men and their partners noted a return of their “personality.” One regained fluency of speech and brain processing that had been severely compromised by ADT. Further research in this area would benefit from use of validated instruments to address subjective response to treatment.
Arguably the most important observation from this study is that TTh was not associated with rapid disease progression. Among men with BCR, with median duration of 33 months of TTh, only one progressed to metastatic disease >5 years after beginning TTh. This compares with 3 years estimates of metastatic disease in men with BCR after RP of 14% for Gleason score 5–7 and 37% for Gleason score 8–10.21 Hruby et al. reported that 70 of 538 men demonstrated biochemical failure after XRT for localized PCa with median follow-up of 50 months. Of these 70 men with biochemical failure, 13 had died and metastases were observed in 5 of the remaining 57 (8.8%).22 Only 30% of men with MET demonstrated progression on follow-up imaging studies by 3–12 months. The overall survival of 79.6% (mortality 21.4%) in the MET group compares with median survival of 47.2 months in the ADT alone arm of the CHAARTED Trial.23 The relevance of the short median PSA doubling times of 8.9 months in BCR and 4.4 months in MET is uncertain, as PSA doubling times are not usually determined in men receiving androgens, particularly since PSA expression is itself androgen-dependent.24
There are several important limitations to this study, including its retrospective nature, multiple forms of TTh treatment, and small sample size. In addition, PCa is a heterogenous disease, and this report includes those with Gleason scores ranging from 6 to 9, which may cloud interpretation of results. Nonetheless, these preliminary results indicate that TTh does not appear to cause precipitous PCa progression in men with BCR and MET. There may be a role for TTh in selected men with BCR, MET, or high-risk disease willing to accept the theoretical risk of hastened disease progression in return for enhanced quality of life.
Conclusion
TTh in men with BCR, MET, and high-risk PCa was associated with symptomatic benefits and low rates of complications, although interpretation of these results must be tempered by small sample size and a heterogeneous population. Well-designed prospective studies are needed to provide better evidence for the potential use of TTh in similarly affected individuals. In the meantime, these results may provide clinicians with a framework to counsel patients who prioritize quality of life over longevity.
-Patrick
[1] liebertpub.com/doi/10.1089/...
Androgens: Clinical Research and Therapeutics Vol. 2, No. 1 Original ArticleOpen AccessCreative Commons license
Testosterone Therapy in Men with Biochemical Recurrence and Metastatic Prostate Cancer: Initial Observations
Abraham Morgentaler, Alejandro Abello, and Glenn Bubley
Published Online:21 Jul 2021doi.org/10.1089/andro.2021....
click on link for full text - including charts
Olaparib for Metastatic Castration-Resistant Prostate Cancer 
