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End of the Line for a Failed Prostate Cancer Drug

— Orteronel misses mark in metastatic hormone-sensitive prostate cancer, after failures in mCRPC

MedpageToday
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The androgen synthesis inhibitor orteronel failed to improve survival in metastatic hormone-sensitive prostate cancer (mHSPC) despite a twofold improvement in progression-free survival (PFS) versus standard androgen-deprivation therapy (ADT), a large randomized trial showed.

Patients randomized to ADT plus orteronel had a median overall survival (OS) of 81 months compared with 70.2 months with ADT plus bicalutamide. The CYP17 inhibitor resulted in a median PFS of 47.6 months as compared with 23.0 months with ADT, and significantly more patients had a prostate-specific antigen (PSA) response with orteronel.

However, the favorable effect on secondary endpoints did not propel the therapy to a protocol-specified 33% improvement in OS, reported Neeraj Agarwal, MD, of University of Utah Huntsman Comprehensive Cancer Center in Salt Lake City, and co-authors, in the .

"The discrepancy between improvement in PFS but not in OS might have occurred because of receipt of subsequent life-prolonging therapy in a large proportion of patients in the control arms," the authors stated. "The primary endpoint of OS evaluated not only the benefit of early addition of orteronel but also the impact of subsequent life-prolonging therapies, including abiraterone acetate [Zytiga], enzalutamide [Xtandi], docetaxel, cabazitaxel [Jevtana], sipuleucel-T [Provenge], and radium-223 [Xofigo]."

"In this study, 77.4% of the patients who progressed in the control arm received subsequent life-prolonging therapies compared with 21-64% of patients in phase III studies in this setting reported since 2013, where the control arm comprised ADT only without recently approved novel agents (nonintensified ADT)," Agarwal and co-authors wrote.

Subsequent life-prolonging therapies in the control arm also might explain the 70-month median OS, the highest ever reported in a nonintensified ADT control arm of contemporary trials in mHSPC, the team added.

The results bring to a conclusion the disappointing clinical trial experience with orteronel, 7 years after two failed phase III trials in metastatic castration-resistant prostate cancer (mCRPC) -- one with 1,100 patients and the other with 1,560 patients -- led Takeda to . The SWOG-1216 trial mHSPC was ongoing at the time and continued to conclusion.

From the same molecular family as abiraterone, orteronel , which minimizes the need for co-administration of steroids to counter diminished cortisol production and associated electrolyte abnormalities, hypertension, and edema. In contrast, abiraterone and requires co-administration of steroids.

When SWOG-1216 was designed, investigators hypothesized that adding orteronel to ADT would improve OS, PFS, and PSA response relative to ADT plus bicalutamide. The researchers randomized 1,313 patients to ADT plus orteronel or bicalutamide and continued follow-up for a median of 4.9 years.

The primary analysis showed almost a 10-month absolute difference in median OS in favor of orteronel, but the difference translated into a 14% reduction in the hazard ratio, as compared with the 33% target included in trial assumptions. The 5-year OS also was similar between treatment arms -- 59.7% with orteronel and 57.9% with conventional hormonal therapy (HR 0.86, 95% CI 0.72-1.02).

Orteronel demonstrated a clear difference in median PFS (47.6 vs 23.0 months), representing a 42% reduction in the hazard for disease progression or death (95% CI 0.51-0.67, P<0.001). Significantly more patients in the orteronel arm achieved a PSA complete response of 0.2 ng/mL (58% vs 44%, P<0.0001).

More grade 3/4 adverse events occurred in the orteronel arm (43% vs 13%). Principal differences included hypertension (20% vs 5%) and fatigue (5% vs 2%).

In a presentation during the 2021 American Society of Clinical Oncology virtual meeting, Agarwal noted the dramatic difference in median OS for the control arm of SWOG-1216 versus other trials of contemporary phase III trials in mHSPC. In four other large randomized trials, median OS in the control groups ranged from 34.7 to 46 months. Median OS in the trials' experimental arms also lagged far behind the 81.0 month median in SWOG-1216 (57.6 to 60 months).

Despite the negative outcome, the trial provided useful information relevant to contemporary treatment of metastatic prostate cancer, said ASCO invited discussant Lisa Horvath, MD, of the Chris O'Brien Lifehouse in Sydney, Australia.

"So what have we learned from this study? TAK-700 [orteronel] is not the same as abiraterone," said Horvath. "This study is similar to the studies in the metastatic castration-resistant space, in which radiological progression-free survival showed a significant difference which was not translated into overall survival. However, this is a well-designed randomized, controlled trial with a high proportion of men of African-American origin, and this is important for translation into the real world."

"It is also the longest overall survival seen in a control group in this setting, which may be due to good prognostic factors, although this is difficult to compare because of the different risk stratification categories that were used," she added. "It does show that in a setting where multiple life-prolonging treatments are available ... that men can live for a very long time."

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

Disclosures

The SWOG-1216 trial was supported by NIH and by Millennium Pharmaceuticals/Takeda.

Agarwal disclosed that he is a member of the Journal of Clinical Oncology edititorial board. He also disclosed relationships with Pfizer, Medivation/Astellas, Bristol Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Exelexis, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Onology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Gilead Sciences, Takeda, Pvizer, Amgen, ORIC Phrmaceuticals, CRISPR Therapeutics, and Arvinas.

Primary Source

Journal of Clinical Oncology

Agarwal N, et al "Orteronel for metastatic hormone-sensitive prostate cancer: A multicenter, randomized, open-label phase III trial (SWOG-1216)" J Clin Oncol 2022; DOI: 10.1200/JCO.21.02517.