Thus, the risk of the primary endpoint was 72% lower with apalutamide versus placebo (median metastasis-free survival, 40.5 vs. 16.2 months, respectively; hazard ratio [HR], 0.28; 95% confidence interval [CI], 0.23 to 0.35; P < .0001), researchers reported at the 2018 ASCO Genitourinary Cancers Symposium1 and simultaneously in the New England Journal of Medicine.2
“These are fantastic, practice-changing data in an area where we have an unmet clinical need,” said study coauthor Simon Chowdhury, MBBS, PhD, a consulting medical oncologist with Guy's and St Thomas' Hospitals, Great Maze Pond, London. Apalutamide occasionally caused rash, but most patients tolerated it well, and his site topped the recruitment list, he said. “To be honest, I usually couldn’t tell who was on placebo and who was on the drug.”No therapies are approved for non-metastatic prostate cancer that becomes resistant to androgen-deprivation therapy (ADT). Patients must wait for metastasis to add treatments, even if their prostate-specific androgen (PSA) doubling time is 10 months or less, indicating a high risk of near-term progression. “This is a very tough situation,” Dr. Chowdhury said. “A lot of people think a rising PSA means they have years and years to go, but a quickly rising PSA is a death sentence for men with castration-resistant prostate cancer [CRPC].”
Apalutamide binds the androgen receptor, preventing its activation by testosterone and other androgens. In a phase II trial of men with high-risk, non-metastatic CRPC, staying on ADT while adding once-daily oral treatment with apalutamide (240 mg) was well-tolerated and led to at least a 50% decline in PSA levels in 89% of cases.3 Furthermore, median metastasis-free survival was not reached after a median follow-up of 28 months, investigators reported in the December 2016 European Urology.3
Accordingly, the randomized, double-blind, phase III SPARTAN trial (NCT01946204) enrolled more than 1,200 men with non-metastatic CRPC whose PSA doubling time was 10 months or less and whose pelvic lymph nodes below the iliac bifurcation measured less than 2 cm.1 Patients were randomly assigned (2:1) to receive apalutamide (240 mg) or placebo while continuing ADT. Every 16 weeks, patients were evaluated for adverse effects and radiographic progression at 322 centers in the United States, Canada, Europe, Australia, Israel, Japan, Korea, and Russia.
Imaging and PSA findings were tracked blindly, including after patients progressed, Eric Small, MD, professor of medicine and chief of the hematology-oncology division at the University of California, San Francisco, said while presenting the findings at ASCO GU.1 Baseline characteristics were well-balanced between groups, he added. Median baseline PSA doubling time was about 4.5 months in each arm, about 17% of patients were node-positive at baseline, and just under three-quarters had received a first-generation anti-androgen therapy.
Apalutamide’s dramatic effect on the primary endpoint spanned prespecified subgroups stratified by PSA level, PSA doubling time, and node status. Treatment also produced consistent, statistically significant improvements across all secondary endpoints, including time to metastasis, progression-free survival, and time to symptomatic progression, Dr. Small said. Compared with the placebo group, the apalutamide group had a 51% lower risk of progression during first subsequent treatment for metastatic CRPC and a 94% lower risk of PSA progression. Levels of PSA fell by at least 50% in 90% of apalutamide recipients versus 2% of the placebo arm.
The interim analysis also linked apalutamide to a 30% reduction in risk of death compared with placebo (HR, 0.7). The 95% CI for estimate did not reach statistical significance, but only 24% of events required to power the analysis had occurred at the time of interim data cutoff, according to Dr. Small. Investigators will perform final, pre-planned, event-driven analyses of overall survival and time to initiation of chemotherapy, he said.
Apalutamide was associated with several grade 3-4 adverse events, including fatigue (0.9% vs. 0.3% in the placebo arm), rash (5.2% vs. 0.3%), weight loss (1.1% vs. 0.3%), falls (1.1% vs. 0.8%), and fractures (2.7% vs. 0.8%), Dr. Small reported. The overall rate of seizure was 0.2% in the apalutamide arm, with no grade 3 or higher events.
Patients in both arms were eligible to receive study-provided abiraterone acetate at the time of distal metastasis. “One of the strengths of this study is that among patients who discontinued study treatment, 78% of the placebo group subsequently received approved treatment for metastatic CRPC,” Dr. Small said.
Taken together, the findings might indicate that apalutamide benefits patients with non-metastatic CRPC more than the current standard of treating after metastasis, Dr. Small said. “Together with its favorable side effects profile, these efficacy data suggest that apalutamide should be considered as a new standard of care for men with high-risk, non-metastatic CRPC,” he concluded.
Dr. Chowdhury agreed: “It’s not that this drug is radically different [than other anti-androgen therapies], but it’s used in a space that's radically different.” Men with CRPC who have a rapid PSA doubling time, but who are otherwise healthy, “should definitely be on this agent,” he said. “You have to look at comorbidities and life expectancy – if it’s short, apalutamide may not be the right approach. But many of these men will live for a long period of time and need their disease controlled so they can continue contributing to their families and to society.”
The U.S. Food and Drug Administration (FDA) has granted apalutamide a Priority Review designation, and its maker, Janssen Pharmaceutical Companies of Johnson & Johnson, has submitted a Marketing Authorisation Application to the European Medicines Agency (EMA). Several more phase III trials are evaluating this agent in the settings of earlier and later-stage prostate cancer.
Written by: Amy Karon, DVM, MPH, MA, Health and medical writer, editor. Doctorate in veterinary medicine, master of public health, and master of arts in journalism, University of Wisconsin-Madison, American Medical Writers Association and the Association of Health Care Journalists
- SPARTAN, a phase 3 double-blind, randomized study of apalutamide (APA) versus placebo (PBO) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC). Presented at: 2018 Genitourinary Cancers Symposium (ASCO GU); February 8-10, 2018; San Francisco, CA, USA. Abstract 161.
- Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med 2018 Feb 8. doi: 10.1056/NEJMoa1715546. [Epub ahead of print]
- Smith MR, Antonarakis ES, Ryan CJ, et al. Phase 2 study of the safety and antitumor activity of Apalutamide (ARN-509), a potent androgen receptor antagonist, in the high-risk nonmetastatic castration-resistant prostate cancer cohort. Eur Urol 2016 Dec;70(6):963-970.
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