Bipolar androgen therapy demonstrated clinically meaningful activity and a good safety profile compared with enzalutamide in asymptomatic men with metastatic castration-resistant prostate cancer who progressed on abiraterone acetate.
Bipolar androgen therapy demonstrated clinically meaningful activity and a good safety profile compared with enzalutamide (Xtandi) in asymptomatic men with metastatic castration-resistant prostate cancer (mCRPC) who progressed on abiraterone acetate (Zytiga), according to findings from the randomized phase 2 TRANSFORMER trial.
Additionally, the findings, which were published in the Journal of Clinical Oncology, revealed that bipolar androgen therapy is able to sensitize men with mCRPC to subsequent antiandrogen therapy.
At a median follow-up of 31.9 months, the median progression-free survival (PFS) was 5.7 months in both the bipolar androgen therapy and enzalutamide arms (HR, 1.14; 95% CI, 0.83-1.55; P = .42). Radiographic PFS was 6.05 months with bipolar androgen therapy vs 8.29 months with enzalutamide (HR, 1.24; 95% CI, 0.87-1.77; P = .2332).
The median overall survival (OS) was not statistically significant at 32.9 months with bipolar androgen therapy vs 29.0 months with enzalutamide (HR, 0.95; 95% CI, 0.66-1.39; P = .8015).
“Although the trial failed to demonstrate superior PFS with [bipolar androgen therapy] over enzalutamide in post-abiraterone CRPC, it demonstrated that [bipolar androgen therapy] is safe, enhances quality of life [QOL], and has efficacy comparable to enzalutamide in this patient population,” wrote the study authors. “However, the most important finding is that post-abiraterone, [bipolar androgen therapy] can markedly improve the magnitude and duration of response to enzalutamide when used as an intervening therapy.”
Antiandrogen therapy with androgen deprivation therapy (ADT) remains the mainstay of treatment for men with mCRPC; however, resistance to these agents is nearly universal and second-generation agents confer modest survival benefits.
Clinical studies with bipolar androgen therapy, a therapy that rapidly cycles between polar extremes of supraphysiologic and near-castrate serum testosterone, showed that the treatment was safe, did not accelerate disease progression, produced sustained prostate-specific antigen (PSA) levels and objective responses, and resensitized patients to subsequent antiandrogens.
As such, the multicenter, open-label TRANSFORMER (Testosterone Revival Abolishes Negative Symptoms, Fosters Objective Response and Modulates Enzalutamide Resistance) trial evaluated the primary end point of clinical or radiographic PFS, with secondary end points of OS, PSA-PFS, PSA decline of 50% or more (PSA50), safety, and quality of life (QOL).
Asymptomatic patients with confirmed mCRPC by CT scan, technetium-99 bone scan, or both were eligible for enrollment. Patients had to have an ECOG performance status (PS) of 0 to 2 and evidence of PSA or radiographic progression after treatment with abiraterone or prednisone.
Exclusion criteria stated that patients who had pain because of mCRPC that required treatment intervention or opioids or who had prior treatment with docetaxel or cabazitaxel (Jevtana) for mCRPC were ineligible.
Overall, 222 patients were assessed for eligibility and 27 were excluded for not meeting inclusion criteria (n = 24) or declining to participate (n = 3).
Eligible patients (n = 195) were randomized 1:1 to receive 400 mg of intramuscular testosterone cypionate once every 28 days (n = 94) or 160 mg of oral enzalutamide daily (n = 101) until clinical or radiographic progression or unacceptable toxicity. Patients also received concurrent and continuous testosterone suppression via surgical castration or luteinizing hormone-releasing hormone agonists or antagonists.
Crossover was not mandated; however, patients with radiographic progression on either arm who continued to meet eligibility requirements were able to cross over to the opposite treatment with the objective of evaluating time to PSA progression and time to second PSA progression from randomization through crossover treatment (PFS2). Overall, 37 patients in the bipolar androgen therapy arm crossed over to receive enzalutamide, and 48 patients in the enzalutamide arm crossed over to receive bipolar androgen therapy .
Of those patients allocated to BAT (n = 94), 5 did not receive the therapeutic intervention because of: not meeting inclusion criteria (n = 1), withdrawn consent before treatment (n = 1), back pain (n = 2), or investigator’s decision (n = 1). Among those allocated to enzalutamide (n = 101), 2 patients withdrew consent before treatment, 1 patient had insurance denial, and 1 had a stroke.
Baseline patient characteristics were generally well balanced between arms. In both arms, patients were a median of 71 years old and predominantly White, with an ECOG PS of 0 and a Gleason score of 9 or 10. Most patients received more than 6 months of prior abiraterone.
Prior therapies included primary radiation, prostatectomy, secondary hormonal therapy, docetaxel, and investigational regimens.
The median total number of metastases was 2 and 55.3% (n = 52) and 61.4% (n = 62) of patients on bipolar androgen therapy and enzalutamide, respectively, had visceral metastases.
Additional results demonstrated that 28.2% (n = 24) of patients receiving bipolar androgen therapy obtained a PSA decline of 50% or greater vs 25.5% (n = 24) of patients receiving enzalutamide. The median time to PSA progression was 2.79 months and 3.81 months, respectively (HR, 1.53; 95% CI, 1.08-2.19; P = .0181).
The objective response rate (ORR) was 24.2% with bipolar androgen therapy vs 4.2% with enzalutamide (P = .072).
A prespecified analysis showed that patients who had a short response to abiraterone of less than 6 months favored bipolar androgen therapy compared with enzalutamide (HR, 0.60; 95% CI, 0.29-1.25), whereas patients with a longer response to abiraterone of 6 months or greater favored enzalutamide compared with BAT (HR, 1.31; 95% CI, 0.93-1.84; Pinteraction = .10). Similar findings were observed regarding OS (<6 months, HR, 0.55; 95% CI, 0.24-1.26; ≥6 months, HR, 1.08; 95% CI, 0.71-1.64; Pinteraction = .14).
Additionally, regarding the cross-over cohort, radiographic progression served as the primary reason for crossover. In this group, 77.8% (n = 28) of patients who crossed over to bipolar androgen therapy from enzalutamide experienced a PSA decline of 50% or greater compared with 21.3% (n = 10) of patients who crossed over to enzalutamide from bipolar androgen therapy. The time to PSA progression was 10.9 months vs 1.1 months, respectively (P = .0001). The objective response rate was 28.6% vs 7.3%, respectively. Finally, PFS2 was 28.2 months vs 19.6 months, respectively (HR, 0.44; 95% CI, 0.22-0.88; P = .0152).
“Sequential BAT [followed by] enzalutamide could be a safe and effective single third-line therapy for men with mCRPC progressing on abiraterone,” the study authors wrote. “Further study is warranted to define the potential for this sequential treatment to produce significant survival improvement in men with CRPC.”
Regarding androgen-receptor expression, baseline blood samples were analyzed from 187 patients. Overall, 41.1% (n = 37) of patients receiving bipolar androgen therapy and 37.1% (n = 36) of patients receiving enzalutamide tested positive for full-length androgen receptor (AR-FL). Within this subgroup, the median PFS was 4.6 months vs 3.0 months respectively (P = .0044). The median OS was 29.6 months compared with 28 months.
Additionally, 12.2% (n = 11) patients receiving bipolar androgen therapy were positive for the truncated ligand-independent AR variant (AR-V7) vs 7.2% (n = 7) of patients receiving enzalutamide. The median PFS in this subgroup was 4.0 months vs 2.5 months, and the median OS was 13.8 months vs 17.3 months, respectively.
Regarding safety during initial treatment, any-grade adverse effects (AEs) occurred in 96.6% of patients on bipolar androgen therapy vs 97.9% of patients on enzalutamide. Of these, 28.1% and 35.1% were grade 3 or 4 events. One patient on the enzalutamide arm experienced a grade 5 event. Additionally, 9.0% of patients in the bipolar androgen therapyarm vs 5.2% of patients in the enzalutamide arm reported an AE that led to trial discontinuation.
The incidence of all-grade AEs was similar between arms and were primarily low grade. However, bipolar androgen therapywas associated with lower rates of fatigue, gastrointestinal events, and constitutional symptoms compared with enzalutamide. The incidence of edema, generalized pain, and sexual AEs was higher with bipolar androgen therapyvs enzalutamide.
Grade 3 or 4 events in the bipolar androgen therapyvs enzalutamide arms, respectively, included fatigue (0% vs 7.2%), generalized pain (3.4% vs 1.0%), edema of the limbs (1.1% vs 0%), back pain (3.4% vs 7.2%), extremity pain (1.1% vs 2.1%), bone pain (0% vs 1.0%), arthralgia (1.1% vs 0%), myalgia (0% vs 1.0%), nausea (1.0% vs 1.0%), anorexia (0% vs 2.1%), hypertriglyceridemia (0%, vs 1.0%), and insomnia (0% vs 1.0%).
AEs of special interest included hematuria, urinary frequency, urinary retention, urinary urgency, hemoglobin increase, mood swings, increased temper/anger, personality change, hypertension, seizures, stroke, thrombolic event, chest pain, palpitations, testicular pain, and breast pain/tenderness, including gynecomastia and hot flashes. Of these, grade 3/4 events were reported in 1 patient on bipolar androgen therapy(hematuria) and 6 patients on enzalutamide (n = 4, hypertension; n = 2, thrombolic).
Notably, patient-reported QOL consistently favored bipolar androgen therapycompared with enzalutamide at 1, 3, and 6 months after treatment initiation. Key domains that were better with bipolar androgen therapyvs enzalutamide included fatigue, and physical and sexual function.