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An extended progression-free interval failed to translate into better overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) treated with two androgen-targeted drugs instead of one, a randomized trial showed.

The population of previously untreated patients had a median OS of 36.2 months with apalutamide (Erleada) and abiraterone (Zytiga) as compared with 33.7 months with abiraterone. In contrast, the hormonal combination resulted in a median progression-free survival (PFS) of 22.6 months versus 16.6 months with abiraterone (P<0.0001), and an updated analysis yielded median PFS values of 24.0 and 16.6 months.

Older patients and those with visceral metastases fared better with apalutamide and abiraterone, as did patients with luminal subtype disease and higher androgen receptor activity, reported Dana E. Rathkopf, MD, of Memorial Sloan Kettering Cancer Center in New York City, during the virtual meeting of the .

"Clinical and biomarker subgroups identified in this analysis will need further exploration to better delineate who might benefit most from the addition of apalutamide to abiraterone in metastatic castration-resistant prostate cancer," Rathkopf said in conclusion.

Despite advances in molecular biology and therapy, mCRPC remains a major unmet clinical need. Though driven by activated androgen receptors and elevated intratumoral androgens, the overall patient population is heterogeneous in terms of androgen receptor resistance and sensitivity, Rathkopf noted.

Apalutamide disrupts androgen receptor signaling, whereas abiraterone inhibits androgen biosynthesis. Simultaneous inhibition of both pathways might provide additional clinical benefit beyond either drug's individual activity, she continued. The randomized phase III tested the hypothesis that two androgen-targeted drugs would be better than one in men with untreated mCRPC.

Investigators in 17 countries randomized 982 patients to receive abiraterone and prednisone with or without apalutamide. The primary endpoint was investigator-assessed radiographic PFS, and OS was a key secondary endpoint.

The trial met the primary endpoint in March 2018 after a median follow-up of 25.7 months, but follow-up continued until a definitive analysis of OS could be performed. The primary analysis showed a statistically significant 31% reduction in the risk of disease progression or death with combined therapy (95% CI 0.58-0.83).

The OS analysis occurred in September 2020, after a median follow-up of 54.8 months. At that point the difference in PFS had increased from less than 6 months to 7.4 months. Nonetheless, median OS did not differ significantly between the two treatment groups (HR 0.95, 95% CI 0.81-1.11). Multiple prespecified secondary and exploratory endpoints were also similar, including initiation of chemotherapy, opioid use, pain, clinical progression, first subsequent anticancer therapy, and second PFS.

More patients treated with both drugs had at least a 50% decline in prostate-specific antigen (PSA) level (79.5% vs 72.9%, P=0.015) and undetectable PSA levels at some point during treatment (24.6% vs 19.2%, P=0.040). However, median time to PSA progression did not differ between the groups (13.8 vs 12.0 months, P=0.076).

Subgroup analysis showed that patients with visceral metastases (n=143) did better with abiraterone plus apalutamide in terms of PFS (HR 0.69, 95% CI 0.45-1.05) and OS (HR 0.76, 95% CI 0.52-1.10), as did the patients ages ≥75 (n=353; HR 0.54, 95% CI 0.40-0.73 and HR 0.75, 95% CI 0.59-0.96, respectively). Consistent with data from prior studies, patients with PAM50 luminal subtype and average or high androgen receptor activity had numerically better PFS (HR 0.70, HR 0.71) and OS (HR 0.84, HR 0.91).

No new or unexpected adverse events (AEs) occurred during the trial. The combination led to more fatigue, hypertension, skin rash, and cardiac disorders. Patient-reported outcomes declined over time in both groups, indicative of disease progression, but did not differ significantly, Rathkopf reported.

The trial left unanswered questions of whether escalation of androgen receptor signaling inhibition improves outcomes and whether continued androgen inhibition after progression is helpful, said invited discussant Joshi J. Alumkal, MD, of the University of Michigan Rogel Cancer Center in Ann Arbor. Prior studies that addressed the questions had produced inconsistent results. Biomarker investigation will play a key role in providing answers.

"Understanding the key drivers of these tumors may provide a roadmap for how to address the most aggressive subsets of CRPC tumors, who appear to do quite poorly, even with ARSI [androgen receptor signaling inhibition] escalation," he said.

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