Androgen Cycling Shows Promise in Castration-Resistant Prostate Cancer | MedPage Today

Androgen Cycling Shows Promise in Castration-Resistant Prostate Cancer | MedPage Today

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Androgen Cycling Shows Promise in Castration-Resistant Prostate Cancer

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— Results comparable to enzalutamide in post-abiraterone setting

by Charles Bankhead, Senior Editor, MedPage Today

A treatment strategy based on manipulation of testosterone levels showed promise as a potential aid for managing castration-resistant prostate cancer (CRPC), according to a randomized proof-of-principle trial.

Following disease progression with abiraterone (Zytiga), treatment with bipolar androgen therapy (BAT) or enzalutamide (Xtandi) led to a median progression-free survival (PFS) of 5.7 months (clinical or radiographic progression). A similar proportion of patients in each treatment arm had at least a 50% reduction in baseline PSA level (PSA50 response), and overall survival (OS) did not differ significantly between the groups, reported Samuel R. Denmeade, MD, of Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, and colleagues.

The median time to PSA progression (PSA-PFS) with enzalutamide increased from 3.8 months after abiraterone to 10.9 months after crossover from BAT (P=0.008). The results suggested BAT might have a role in altering the adaptive process that transforms hormone-sensitive prostate cancers into CRPC, they stated in the Journal of Clinical Oncology.

"I think the key result of this study is that sequencing testosterone and then anti-testosterone therapy, in this case enzalutamide, seems to be the ideal way [to modify the adaptive process]," Denmeade told MedPage Today. "A tumor seems to be sensitive and then adapts and becomes insensitive, so you switch treatments."

Background

As a therapeutic concept, BAT evolved from the long-recognized conversion of prostate cancer from hormone-sensitive to hormone (castration)-resistant disease during prolonged androgen deprivation therapy (ADT). Therapeutic resistance to ADT is almost universal, Denmeade and colleagues noted. Newer androgen-receptor (AR) inhibitors have become standard second-line therapy, but resistance increases with each line of AR-directed treatment.

In response to low-androgen conditions created by antiandrogen therapy, prostate cancer cells can develop resistance by means of adaptive upregulation of AR, the authors continued. Preclinical studies showed that the adaptive process can make prostate cancer cells vulnerable to supraphysiologic testosterone levels. Episodic exposure to supraphysiologic testosterone can induce downregulation of AR and potential resensitization of cancer cells to androgen-ablative treatment.

Preliminary clinical investigations demonstrated the feasibility and safety of BAT or rapid cycling between supraphysiologic and near-castrate serum levels of testosterone. The work formed the basis for the multicenter randomized phase II TRANSFORMER trial to compare BAT and enzalutamide in metastatic CRPC that had progressed on abiraterone but remained asymptomatic.

The study involved 195 men who received intramuscular testosterone once every 28 days or daily enzalutamide. Patients in both arms were concurrently managed with testosterone suppression by surgical or medical castration.

The primary endpoint was clinical or radiographic PFS. Crossover was allowed at disease progression. Secondary endpoints included OS, PSA50 and objective response rates, PFS from randomization through crossover (PFS2), safety, and quality of life (QoL). All analyses were based on the intention-to-treat principle and included all randomized patients.

Key Results, Future Directions

The primary analysis showed a median PFS of 5.6 months with BAT and 5.7 months with enzalutamide (HR 1.13, 95% CI 0.82-1.57). At data cutoff a year later, median PFS was identical in the two treatment arms (5.7 months, HR 1.4, 95% CI 0.83-1.55). A prespecified analysis showed the PFS results did not differ by duration of response to prior abiraterone (<6 months vs ≥6 months) but that a shorter response numerically favored BAT and a longer response favored enzalutamide.

Median OS did not differ significantly but favored BAT (32.9 vs 29.0 months). Consistent with the PFS data, shorter PFS with abiraterone favored BAT and longer PFS with prior abiraterone favored enzalutamide.

PSA50 response rate was similar in the two treatment arms (28.2% with BAT, 25.5% with enzalutamide). The time to first PSA progression was short in both groups but favored enzalutamide (3.8 vs 2.8 months, HR 1.51, 95% CI 1.06-2.16, P=0.02).

At clinical or radiographic progression, patients could cross over to the opposite therapy, following a 28-day washout period. Crossover was limited to patients who remained asymptomatic but excluded patients who had pain-related clinical progression.

The authors reported that 37 (39.3%) patients in the BAT arm crossed over to enzalutamide and 48 (47.6%) crossed over from enzalutamide to BAT. More than 90% of patients who crossed over did so because of radiographic progression. In general, patients who crossed over from enzalutamide to BAT fared better as compared with the opposite crossover:

  • OS: 37.1 vs 30.2 months
  • Objective response: 28.6% vs 7.3% (P=0.03)
  • PSA50 (unverified): 77.8% vs 21.3%
  • PSA-PFS: 10.9 vs 1.1 months (P=0.0001)
  • PFS2: 28.2 vs 19.6 months (P=0.015)

Adverse event (AE) rates were similar in both treatment arms and were primarily grade 1/2. Rates of grade 3/4 AEs were 28.1% with BAT and 35.1% with enzalutamide. Serious AEs occurred in 19.1% of the BAT arm and 20.6% of the enzalutamide group. More patients discontinued BAT because of AEs as compared with enzalutamide (9.0% vs 5.2%).

Enrollment has already begun for a follow-up trial to evaluate multiple cycles of alternating testosterone extremes (supraphysiologic and castrate or near-castrate levels). BAT might also have a role in conjunction with immunotherapy as preliminary data have suggested a potential priming effect of BAT to make prostate cancer cells more responsive to immunotherapy.

"We're at a point where we're trying to understand the best way to use this treatment," said Denmeade. "We're still working on how to incorporate testosterone into the treatment paradigm. We think it has the potential to augment and extend the response."

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    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined MedPage Today in 2007.

Disclosures

The study was supported by the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in collaboration with the Department of Defense.

Denmeade disclosed a relevant relationship with Sophiris Bio. Co-authors disclosed multiple relevant relationships with industry.

 

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