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Apalutamide slows development of prostate cancer metastases
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Apalutamide conferred a 72% reduced risk for metastasis or death compared with placebo among men with nonmetastatic castration-resistant prostate cancer at high risk for developing metastatic disease, according to the randomized phase 3 SPARTAN study scheduled for presentation at the Genitourinary Cancers Symposium.
“To date there has been no therapy approved for this disease state, and the aim of this study was to see if the development of metastases in the transition from nonmetastatic to metastatic could be slowed,” Eric J. Small, MD, FASCO, professor of medicine at University of California, San Francisco, said during a press cast. “Frequently, these patients receive unproven, older generation, second-line hormone therapy, and none of those agents have demonstrated an impact on outcome. It is a big unmet need.”
As HemOnc Today previously reported, apalutamide (ARN-509; Janssen, Aragon Pharmaceuticals) — which inhibits the action of testosterone in prostate cancer cells and prevents androgen from binding to the androgen receptor — received priority review by the FDA in January for the treatment of nonmetastatic castration-resistant prostate cancer.
Some physicians advocate active surveillance for these patients; however, men whose PSA score rapidly rises — based on a PSA doubling time of less than 8 to 10 months — while on androgen deprivation therapy are at increased risk for developing metastases or death. This group represented the 1,207 men enrolled in the SPARTAN study conducted at 332 institutions worldwide.
Researchers randomly assigned men with nonmetastatic castration-resistant prostate cancer who had stopped responding to ADT and were at high risk for metastasis based on PSA doubling time to 240 mg daily apalutamide or placebo added to ongoing ADT.
At the time of development of metastases, patients received standard second therapies at their physician’s discretion and had an option to receive on-study abiraterone acetate (Zytiga, Janssen) and prednisone.
Metastasis-free survival — defined as the time from randomization to first radiographic distant metastasis or death — served as the primary endpoint. Time to metastasis, PFS, time to symptomatic progression and OS served as secondary endpoints.
The median PSA doubling time at study entry was approximately 4.5 months in both the apalutamide and placebo groups.
Apalutamide decreased the risk for metastasis and death by 72% compared with placebo (HR = 0.28; 95% CI, 0.23-0.35) and significantly prolonged the median metastasis-free survival by 2 years (40.5 months vs. 16.2 months).
Researchers also noted a trend favoring improved OS for men receiving apalutamide, although the difference was not statistically significant.
Time to metastasis, PFS and time to symptomatic progress also improved. At a median follow-up of 20.3 months, 61% of the apalutamide group and 30% of the placebo group remained on treatment.
Following the analysis of metastasis-free survival, study treatment was unblinded in July 2017 following the recommendations of an independent data monitoring committee, and all patients were offered open-label apalutamide.
Of those whose disease progressed, 80% of placebo patients and 52% of apalutamide patients received therapy for metastatic disease.
Apalutamide was well tolerated, with 10.7% of men discontinuing treatment due to adverse events, compared with 6.3% of men receiving placebo. Men who received apalutamide in addition to ADT maintained their quality-of-life scores.
“We concluded that apalutamide reduced the risk [for] metastases by 72% and prolonged the median metastases-free survival in these men by more than 2 years,” Small said. “The trend is certainly encouraging. Overall, these data suggest that apalutamide should now be considered a new standard of care for men with high-risk, nonmetastatic castration-resistant prostate cancer.”
Researchers noted future studies should analyze molecular and circulating markers from blood samples to identify patients who benefit most from apalutamide. – by Chuck Gormley
Disclosures: Aragon Pharmaceuticals funded the study. Small reports consultant/advisory roles with Fortis, Gilead Sciences and Valeant Pharmaceuticals International; stock ownership in Fortis and Harpoon Therapeutics; honoraria from Janssen-Cilag; and researching funding from Janssen. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Sumanta K. Pal, MD
As we look at these data, it is critical to understand the patient population in the trial. Specifically, despite being maintained on conventional hormonal agents, the PSA blood markers for prostate cancer in these patients rose nonetheless. Curiously, however, these patients had no visible evidence of spread. Until the results of studies presented at this meeting, there has really been no obvious standard of care for these patients. In the dataset presented by Small and colleagues, we see that apalutamide — a very potent hormonal therapy — delayed the risk for metastases or death by 72%, a very clinically meaningful finding. Moreover, the drug appeared to be very well tolerated.
It will be interesting to see a different but somewhat related trial — PROSPER — which employs a similar design, randomly assigning patients to either enzalutamide (Xtandi; Astellas, Medivation) — as opposed to apalutamide — or placebo. We know from a press release issued in September 2017 that this study also showed a significant delay in the time to onset of metastatic disease. It will be interesting to juxtapose these data once they are available. Enzalutamide is a drug familiar to the prostate cancer community, given existing approvals in the setting of more advanced disease. The familiarity that oncologists already have with enzalutamide may help with clinical adoption.
It also is important to bear in mind the disease state of nonmetastatic castration-resistant prostate cancer with a rising PSA failing to respond to conventional hormone therapy may potentially be a shrinking population. This is because of improving imaging modalities at our disposal to detect metastatic disease. The SPARTAN trial used a more conventional imaging approach with CT scans and technetium bone scan. Although this is the standard, imaging techniques such as fluciclovine PET and prostate-specific membrane antigen PET may potentially improve our ability to detect disease spread earlier and, thereby, change our management strategy.
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