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SAN FRANCISCO -- Men with non-metastatic castration-resistant prostate cancer (nmCRPC) had a 2-year delay in the time to metastatic progression when treated with the new-generation androgen-receptor inhibitor apalutamide, a large randomized trial showed.

Patients randomized to apalutamide had a median metastasis-free survival (MFS) of 40.5 months versus 16.2 months for placebo treatment. The difference represented a 72% reduction in the hazard for metastatic progression or death, according to Eric Small, MD, of the University of California San Francisco, and colleagues.

Time to metastasis (TTM), progression-free survival (PFS), symptomatic progression, and PFS after subsequent therapy (PFS2) all favored apalutamide, Small reported at a press briefing prior to the Genitourinary Cancers Symposium (GUCS).

"Apalutamide was associated with a reduced risk of death, but that was not significant at this early interim analysis and will continue to be followed. The trend was certainly encouraging," he said. "Treatment with apalutamide was generally well tolerated with no impact on quality-of-life [QoL] scores and with low rates of discontinuation due to treatment-related adverse events. Overall, these data suggest that apalutamide should be considered as a new standard of care for men with nonmetastatic castration-resistant prostate cancer."

The results were consistent with those of the randomized PROSPER trial with enzalutamide (Xtandi), which also will be reported at GUCS, said press briefing moderator Sumanta Pal, MD, of City of Hope in Duarte, California. The abstract for the PROSPER trial showed a median MFS of 37 months for men treated enzalutamide (Xtandi) versus 15 months with placebo. Patients in both groups continued existing androgen deprivation therapy (ADT) after randomization.

"Until the results of studies presented at this meeting, there's really been no obvious standard of care for these patients," said Pal.

Noting that enzalutamide already has approval for more advanced prostate cancer, Pal added, "The familiarity that oncologists already have with enzalutamide may help with clinical adoption."

However, the patient population targeted by the SPARTAN and PROSPER studies could be shrinking, Pal continued. SPARTAN investigators used conventional imaging modalities (CT and technetium bone scan) to assess patients' status at enrollment and during the trial. Some newer forms of PET imaging may improve the ability to detect disease spread earlier, leading to early changes in clinical management, he said.

Metastatic CRPC remains uniformly fatal, associated with a median survival of about 2.5 years, Small noted. The condition arises in two way: metastatic hormone-sensitive prostate cancer and nmCRPC. Both conditions afford opportunities for interventions that delay or prevent progression to mCRPC, although as Pal noted, nmCRPC currently has no standard of care.

The primary objective of the SPARTAN trial was to determine whether treatment with apalutamide could delay development of metastases and the transition from nonmetastatic to metastatic CRPC. Apalutamide has a that could help accomplish the objective:

• Prevention of androgen binding to receptor
• Prevention of androgen receptor translocation to the nucleus
• Blocking androgen receptor-mediated DNA transcription

Investigators at 332 centers worldwide enrolled 1,207 patients who had a baseline PSA doubling time of less than 5 month. The patients were randomized 2:1 to daily apalutamide or placebo, in addition to continuous ADT. The primary endpoint was MFS. Treatment continued until disease progression, and then patients had the option to switch to abiraterone (Zytiga) plus prednisone.

The trial ended prematurely after a planned interim analysis showed the trial had met the primary endpoint. The results showed that treatment with apalutamide was associated with a significant reduction in the hazard for MFS (95% CI 0.23-0.35, P<0.001). Small did not report results for secondary endpoints (TTM, PFS, and symptomatic progression) but said all were significantly improved in the apalutamide group versus the placebo group.

After a median follow-up of 20.3 months, the survival data remained immature to determine whether apalutamide treatment would lead to improved survival, said Small. However, the interim analysis showed a favorable trend in favor of apalutamide (P=0.07).

Apalutamide was generally well tolerated, as adverse events rates were similar in the two groups. Rates of discontinuation because of adverse events were 10.7% in the apalutamide group and 6.3% in the placebo group. Baseline health-related QoL scores were similar in the two groups and maintained throughout the study.

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