High dose testosterone injections combined with androgen deprivation for men with advanced prostate cancer

Description

Off-label use of an FDA-approved drug, testosterone cypionate, as therapy for castrate resistant prostate cancer. Metastatic prostate cancer is curable if found within the prostate, but incurable once it has spread to other organs.

Castration removes major growth / survival factors and is a form of “shock therapy” for prostate cancer. However, after initial prostate cancer cell death comes an adaptation phase, followed by a resistance phase characterized by marked increases in androgen receptor activity.

Prostate cancer cells have a “sweet spot”, a zone of tolerance to androgen receptor perturbation / activity. Besides castration, prostate cancer cells can get shocked by excessively high testosterone levels. Studies show equal growth inhibition with anti-androgen and high androgen treatment. The testosterone dose is critical; at low doses there is stimulation of prostate cancer growth whereas at high doses there is prostate cancer growth suppression and apoptosis. Several mechanism have been proposed for the androgen induced growth inhibition/death in prostate cancer cells.

These data may have clinical implications for both castration sensitive and castration resistant prostate cancer patients. In castration sensitive patients, standard intermittent androgen deprivation therapy may improve quality of life and sexual function. The disadvantage is variable and slow testosterone recovery, which gives prostate cancer cells time to adapt to changing testosterone levels. To circumvent this, “bipolar androgen therapy (BAT)” has been tested, where injections of testosterone cypionate are given once a month. This results in supraphysiological testosterone levels of >1,500 ng/dL (52.5 nmol/L) followed by a rapid drop in testosterone levels down to <100 ng/dL (3.5 nmol/L). This rapid cycling between polar testosterone extremes can disrupt adaptation to low androgen levels and delay development of resistance to androgen deprivation therapy, while improving quality of life.

In the “BATMAN” study, BAT was tested in men with androgen-ablation naïve prostate cancer1. Asymptomatic patients with hormone-sensitive prostate cancer and low metastatic burden or non-metastatic biochemically recurrent disease were enrolled. Following 6 months of androgen deprivation therapy, those with a PSA <4 ng/mL received alternating 3-month cycles of BAT and androgen deprivation therapy. BAT was administered as intramuscular testosterone cypionate or enanthate 400 mg on days 1, 29, and 57. ADT was continued throughout the study to allow rapid cycling of testosterone from near castrate to supraphysiologic levels following testosterone injections. The primary endpoint was the percent of patients with a PSA <4 ng/mL after 18 months. Secondary endpoints included radiographic response and quality of life. Twenty-nine of 33 patients received BAT following the androgen deprivation therapy lead-in. The primary endpoint was met, with 17/29 men (59%, 90% confidence interval: 42-74%) having a PSA <4 ng/ml at 18 months. Ten patients receiving BAT had Response Evaluation Criteria in Solid Tumors (RECIST) evaluable disease, and eight (80%) objective responses were observed (four complete; four partial). Three patients progressed per RECIST criteria and three had unconfirmed progression on bone scan. Men treated with 6-month of androgen deprivation therapy had improved quality of life following the first cycle of BAT as measured by the SF-36, FACT-P, and IIEF surveys. It was concluded that BAT demonstrated preliminary efficacy in men with hormone-sensitive prostate cancer following 6-month of androgen deprivation therapy. BAT may improve quality of life and sexual function in men treated with androgen deprivation therapy.

In castration resistant prostate cancer patients, BAT may disrupt the adaptive autoregulation of androgen receptors. Adaptive downregulation of androgen receptor expression may re-sensitize castration resistant prostate cancer. In another study, Dr. Denmeade’s group treated 16 asymptomatic patients with castrate resistant prostate cancer with low to moderate metastatic burden with testosterone cypionate (400 mg intramuscular; day 1 of 28) and etoposide (100 mg oral daily; days 1 to 14 of 28). After three cycles, those with a declining prostate-specific antigen (PSA) continued on intermittent testosterone therapy monotherapy. Castrating therapy was continued to suppress endogenous testosterone production, allowing for rapid cycling from supraphysiologic to near-castrate serum testosterone levels, to achieve the bipolar androgen therapy effect. BAT was well tolerated and resulted in high rates of PSA (7 of 14 evaluable patients) and radiographic responses (5 of 10 evaluable patients). Although all men showed eventual PSA progression, four men remained on BAT for ≥1 year. All patients (10 of 10) demonstrated PSA reductions upon receiving androgen-ablative therapies after BAT, suggesting that BAT may also restore sensitivity to androgen deprivation therapy. It was concluded that BAT shows promise as treatment for castrate resistant prostate cancer and should be further evaluated in larger trials.

In the RESTORE study (RE-sensitizing with Supraphysiologic Testosterone to Overcome REsistance) BAT was tested in 30 men with metastatic prostate cancer progression despite androgen deprivation therapy with enzalutamide3. Nine (30%) of 30 patients achieved a PSA50 after BAT. 29 patients completed bipolar androgen therapy and 21 proceeded to enzalutamide rechallenge, of whom 15 (52%) achieved a PSA50 response. During BAT, the only grade 3-4 adverse event occurring in more than one patient was hypertension (three [10%] patients). Other grade 3 or worse adverse events occurring during BAT in one [3%] patient each were pulmonary embolism, myocardial infarction, urinary obstruction, gallstone, and sepsis. During enzalutamide retreatment, no grade 3-4 toxicities occurred in more than one patient. No treatment-related deaths were reported during either BAT or enzalutamide retreatment. It was concluded that BAT is a safe therapy that results in responses in asymptomatic men with metastatic castration-resistant prostate cancer and also resensitisation to enzalutamide in most patients undergoing rechallenge3. Further studies with BAT are needed to define the potential clinical role for BAT in the management of metastatic castration-resistant prostate cancer and the optimal strategy for sequencing between androgen and antiandrogen therapies in metastatic castration-resistant prostate cancer to maximise therapeutic benefit to patients.

The TRANSFORMER trial (Testosterone Revival Abolishes Negative Symptoms, Fosters Objective Response and Modulates Enzalutamide Resistance) is a randomized phase II Study comparing BAT vs. enzalutamide in asymptomatic men with castration resistant metastatic prostate cancer. Study will be completed in December 2018.

The take home points from Dr. Denmeade’s presentation are:

  • Bipolar androgen therapy (BAT) can be given safely to asymptomatic men with castrate resistant prostate cancer.
  • Radiographic response and PSA response is observed in some men.
  • BAT may re-sensitise castrate resistant prostate cancer to androgen deprivation therapies.
  • BAT improves quality of live.

 

Speakers

Prof. Dr. med. Marija Pfeifer

Samuel Denmeade
John Hopkins University School of Medicine, Baltimore, MD

References

  • Schweizer MT, Wang H, Luber B, Nadal R, Spitz A, Rosen DM, Cao H, Antonarakis ES, Eisenberger MA, Carducci MA, Paller C, Denmeade SR. Bipolar Androgen Therapy for Men With Androgen Ablation Naïve Prostate Cancer: Results From the Phase II BATMAN Study. Prostate. 2016 Sep;76(13):1218-26. Return to content
  • Schweizer MT, Antonarakis ES, Wang H, Ajiboye AS, Spitz A, Cao H, Luo J, Haffner MC, Yegnasubramanian S, Carducci MA, Eisenberger MA, Isaacs JT, Denmeade SR. Effect of bipolar androgen therapy for asymptomatic men with castration-resistant prostate cancer: results from a pilot clinical study. Sci Transl Med. 2015 Jan 7;7(269):269ra2. Return to content
  • Teply BA, Wang H, Luber B, Sullivan R, Rifkind I, Bruns A, Spitz A, DeCarli M, Sinibaldi V, Pratz CF, Lu C, Silberstein JL, Luo J, Schweizer MT, Drake CG, Carducci MA, Paller CJ, Antonarakis ES, Eisenberger MA, Denmeade SR. Bipolar androgen therapy in men with metastatic castration-resistant prostate cancer after progression on enzalutamide: an open-label, phase 2, multicohort study. Lancet Oncol. 2018 Jan;19(1):76-86 Return to content