Final Analysis of SPARTAN Study

November 6, 2020

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Final Analysis of SPARTAN Study Includes Overall Survival Data on ERLEADA® (apalutamide) in Patients With Non-Metastatic Castration-Resistant Prostate Cancer: What Does This Mean for Treatment?

In American men, prostate cancer is the most common form of cancer, other than skin cancer, and the second-leading cause of cancer death.1 One in 9 men will be diagnosed with the disease in his lifetime.1 Some will be diagnosed with a particular form of the disease known as non-metastatic castration-resistant prostate cancer (nmCRPC), which is disease that has not spread to other parts of the body, but no longer responds to medical or surgical treatment that lowers testosterone.2

Within recent years, the US Food & Drug Administration (FDA) has approved multiple treatment options for patients with nmCRPC. These treatment options help delay metastasis, which is critical3 because the relative 5-year survival rate for patients diagnosed at distant-stage prostate cancer is 31%.4 In 90% of men, once prostate cancer metastasizes, it will spread to the bone, increasing the likelihood of pain, pathologic fractures, bone marrow failure, and spinal cord compression.5

One treatment option is ERLEADA® (apalutamide), the first FDA-approved therapy to treat nmCRPC, based on results from the Phase 3 SPARTAN clinical trial.6,7 ERLEADA® is also approved for the treatment of patients with metastatic castration-sensitive prostate cancer (mCSPC) based on results from the Phase 3 TITAN study.6,8

The SPARTAN trial was a Phase 3, randomized, double-blind, placebo-controlled, multicenter study that evaluated ERLEADA® plus androgen-deprivation therapy (ADT) in patients with nmCRPC who had a prostate-specific antigen (PSA) doubling time less than or equal to 10 months.7,9 The SPARTAN study enrolled 1207 patients who were randomized 2:1 to receive either ERLEADA® orally at a dose of 240 mg once daily plus ADT (n=806) or placebo once daily plus ADT (n=401).9 Results from the primary analysis showed that, compared with placebo plus ADT, ERLEADA® plus ADT met the trial’s primary endpoint of metastasis-free survival (MFS), prolonging median MFS by more than 2 years (difference of 24.3 months) and reduced the risk of metastasis by 72% (HR=0.28; 95% CI, 0.23-0.35; P<0.0001).6 The SPARTAN primary analysis was first presented at the 2018 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU) and simultaneously published in The New England Journal of Medicine.

While MFS is the primary endpoint in the SPARTAN trial, overall survival (OS), a secondary endpoint in the SPARTAN trial, may provide the most objective and clear measure of survival benefit.10 OS data from the SPARTAN trial were not mature at the time of the final MFS analysis (24% of the required number of events).11 The final analysis, which was presented at the ASCO 2020 Virtual Scientific Program, included OS data, a secondary endpoint.8 These data, published in European Urology, are not included in the ERLEADA® full Prescribing Information.

The SPARTAN final analysis demonstrated that ERLEADA® plus ADT significantly improved OS, compared with ADT alone, in patients with nmCRPC who were at high risk of developing metastases.11 Specifically, ERLEADA® plus ADT demonstrated a median OS that was significantly longer than seen for placebo plus ADT: 73.9 months compared with 59.9 months [HR=0.78; 95% CI; P=0.016 (the P value for OS confirmed a statistically significant improvement of OS, crossing the prespecified O’Brien-Fleming boundary of 0.046)].11 Median treatment duration was 21.4 months longer for patients treated with ERLEADA® plus ADT (32.9 months) compared with those treated with placebo plus ADT (11.5 months).11

Treatment with ERLEADA® plus ADT significantly delayed patients’ time to cytotoxic chemotherapy by 37%, a secondary endpoint, compared with placebo plus ADT (HR=0.63; 95% CI [0.49–0.81]; P=0.0002).11

Grade 3/4 treatment-emergent adverse events of special interest for ERLEADA® plus ADT were rash (5.2%), fractures (4.9%), falls (2.7%), hypothyroidism (0%) and seizures (0%).11 Safety and tolerability of ERLEADA® is consistent and as reported previously. The most common adverse reactions (≥10%) in ERLEADA®-treated patients (≥2% over placebo) from the randomized placebo-controlled clinical trials (SPARTAN and TITAN) were fatigue, arthralgia, rash, decreased appetite, fall, decreased weight, hypertension, hot flush, diarrhea, and fracture.6

The final analysis of SPARTAN demonstrated that, in addition to improved MFS and time to symptomatic progression reported previously, ERLEADA® plus ADT improved OS and lengthened time to initiation of cytotoxic chemotherapy in patients with nmCRPC. With additional Phase 3 registrational trials underway, SPARTAN has the longest follow-up period (52 months) of the registrational trials that supported indications for the treatment of nmCRPC.12,13,14,15,16

ERLEADA® IMPORTANT SAFETY INFORMATION6

WARNINGS AND PRECAUTIONS

Ischemic Cardiovascular Events — In a randomized study (SPARTAN) of patients with nmCRPC, ischemic cardiovascular events occurred in 4% of patients treated with ERLEADA® and 3% of patients treated with placebo. In a randomized study (TITAN) in pa- tients with mCSPC, ischemic cardiovascular events occurred in 4% of patients treated with ERLEADA® and 2% of patients treated with placebo. Across the SPARTAN and TITAN studies, 6 patients (0.5%) treated with ERLEADA® and 2 patients (0.2%) treated with placebo died from an ischemic cardiovascular event. Patients with current evidence of unstable angina, myocardial infarction, or congestive heart failure within 6 months of randomization were excluded from the SPARTAN and TITAN studies. Ischemic cardiovascular events, including events leading to death, occurred in patients receiving ERLEADA®. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Consider discontinuation of ERLEADA® for Grade 3 and 4 events.

Fractures — In a randomized study (SPARTAN) of patients with nmCRPC, fractures occurred in 12% of patients treated with ERLEADA® and in 7% of patients treated with placebo. In a randomized study (TITAN) of patients with mCSPC, fractures occurred in 9% of patients treated with ERLEADA® and in 6% of patients treated with placebo. Evaluate patients for fracture risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents.

Falls — In a randomized study (SPARTAN), falls oc- curred in 16% of patients treated with ERLEADA® compared with 9% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Falls occurred in patients receiving ERLEADA® with increased frequency in the elderly. Evaluate patients for fall risk.

Seizure — In 2 randomized studies (SPARTAN and TITAN), 5 patients (0.4%) treated with ERLEADA® and 1 patient treated with placebo (0.1%) experienced a seizure. Permanently discontinue ERLEADA® in patients who develop a seizure during treatment. It is unknown whether anti-epileptic medications will prevent seizures with ERLEADA®. Advise patients of the risk of developing a seizure while receiving ERLEADA® and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others.

Embryo-Fetal Toxicity — The safety and efficacy of ERLEADA® have not been established in females. Based on its mechanism of action, ERLEADA® can cause fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of ERLEADA® [see Use in Specific Populations (8.1, 8.3)].

ADVERSE REACTIONS

Adverse Reactions — The most common adverse reactions (≥10%) that occurred more frequently in the ERLEADA®-treated patients (≥2% over placebo) from the randomized placebo-controlled clinical trials (TITAN and SPARTAN) were fatigue, arthralgia, rash, decreased appetite, fall, weight decreased, hypertension, hot flush, diarrhea, and fracture.

Laboratory Abnormalities — All Grades (Grade 3-4)

  • Hematology — In the TITAN study: white blood cell decreased ERLEADA® 27% (0.4%), placebo 19% (0.6%). In the SPARTAN study: anemia ER- LEADA® 70% (0.4%), placebo 64% (0.5%); leukopenia ERLEADA® 47% (0.3%), placebo 29% (0%); lymphopenia ERLEADA® 41% (2%), placebo 21% (2%)
  • Chemistry — In the TITAN study: hypertriglyc- eridemia ERLEADA® 17% (3%), placebo 12% (2%). In the SPARTAN study: hypercholesterolemia ERLEADA® 76% (0.1%), placebo 46% (0%); hyperglycemia ERLEADA® 70% (2%), placebo 59% (1%); hypertriglyceridemia ERLEADA® 67% (2%), placebo 49% (0.8%); hyperkalemia ERLEADA® 32% (2%), placebo 22% (0.5%)

Rash — In 2 randomized studies, rash was most commonly described as macular or maculopapular. Adverse reactions of rash were 26% with ERLEADA® vs 8% with placebo. Grade 3 rashes (defined as cov- ering >30% body surface area [BSA]) were reported with ERLEADA® treatment (6%) vs placebo (0.5%). The onset of rash occurred at a median of 83 days. Rash resolved in 78% of patients within a median of 78 days from onset of rash. Rash was commonly managed with oral antihistamines, topical corticosteroids, and 19% of patients received systemic corticosteroids. Dose reduction or dose interruption occurred in 14% and 28% of patients, respectively. Of the patients who had dose interruption, 59% experienced recurrence of rash upon reintroduction of ERLEADA®.

Hypothyroidism — In 2 randomized studies, hypo- thyroidism was reported for 8% of patients treated with ERLEADA® and 2% of patients treated with placebo based on assessments of thyroid-stimulating hormone (TSH) every 4 months. Elevated TSH occurred in 25% of patients treated with ERLEADA® and 7% of patients treated with placebo. The median onset was at the first scheduled assessment. There were no Grade 3 or 4 adverse reactions. Thyroid replacement therapy, when clinically indicated, should be initiated or dose-adjusted.

Effect of Other Drugs on ERLEADA® — Co-administration of a strong CYP2C8 or CYP3A4 inhibitor is predicted to increase the steady-state exposure of the active moieties. No initial dose adjustment is necessary; however, reduce the ERLEADA® dose based on tolerability [see Dosage and Administration (2.2)].

Effect of ERLEADA® on Other Drugs — ERLEADA® is a strong inducer of CYP3A4 and CYP2C19, and a weak inducer of CYP2C9 in humans. Concomitant use of ERLEADA® with medications that are primar- ily metabolized by CYP3A4, CYP2C19, or CYP2C9 can result in lower exposure to these medications. Substitution for these medications is recommended when possible or evaluate for loss of activity if medi- cation is continued. Concomitant administration of ERLEADA® with medications that are substrates of UDP-glucuronosyl transferase (UGT) can result in decreased exposure. Use caution if substrates of UGT must be co-administered with ERLEADA® and evaluate for loss of activity.

P-gp, BCRP or OATP1B1 substrates — Apalutamide is a weak inducer of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1) clinically. Concomitant use of ERLEADA® with medications that are substrates of P-gp, BCRP, or OATP1B1 can result in lower exposure of these medications. Use caution if substrates of P-gp, BCRP or OATP1B1 must be co-administered with ERLEADA® and evaluate for loss of activity if medication is continued.

Please see the full Prescribing Information for ERLEADA®.

REFERENCES:
  1. Cancer.org. Key statistics for prostate cancer: Prostate cancer facts. Accessed September 2020.​
  2. Scher HI, et al. Trial design and objectives for castration-resistant prostate cancer: Updated recommendations from the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. 2016;34:1402-1418.
  3. El-Amm J and Aragon-Ching JB. The current landscape of treatment in non-metastatic castration-resistant prostate cancer. Clin Med Insights Oncol. 2019;13:1-5.
  4. Cancer.org. Survival rates for prostate cancer. Accessed September 2020.​
  5. Saad F, et al. The 2015 CUA0CUOG guidelines for the management of castration-resistant prostate cancer (CRPC). Can Urol Assoc J. 2015;9(3-4):90-96. Accessed September 2020.
  6. ERLEADA® (apalutamide) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.
  7. Smith MR, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018; 378:1408-1418.
  8. Chi K, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381:13-24.
  9. Small E, et al. Final survival results from SPARTAN, a phase 3 study of apalutamide (APA) vs placebo (PBO) in patients (pts) with non- metastatic castration-resistant prostate cancer (nmCRPC). Accessed September 2020.
  10. Zhuang SH, et al. Overall survival: A gold standard in search of a surrogate. Cancer J. 2009; 15(5):395-400.
  11. Smith MR, et al. Apalutamide and overall survival in prostate cancer. Eur Urol (2020).
  12. Clinicaltrials.gov. An efficacy and safety study of apalutamide (JNJ- 56021927) in combination with abiraterone acetate and prednisone versus abiraterone acetate and prednisone in participants with chemotherapy-naive metastatic castration-resistant prostate cancer (ACIS). Accessed September 2020.
  13. Clinicaltrials.gov. An efficacy and safety study of apalutamide (JNJ- 56021927) in high-risk prostate cancer subjects receiving primary radiation therapy (ATLAS). Accessed September 2020.
  14. Clinicaltrials.gov. A study of apalutamide in participants with high- risk, localized or locally advanced prostate cancer who are candidates for radical prostatectomy (PROTEUS). Accessed September 2020.
  15. Sternberg C, et al. Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2020;382:2197-2206.
  16. Fizazi K, et al. Overall survival (OS) results of phase III ARAMIS study of darolutamide (DARO) added to androgen deprivation therapy (ADT) for nonmetastatic castration-resistant prostate cancer (nmCRPC). Accessed September 2020.

This supplement is sponsored by Janssen Biotech, Inc.

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