by Dr. C.H. Weaver M.D. updated 5/2019
The U.S. Food and Drug Administration (FDA) has expanded the approved use of Zytiga® (abiraterone) to treat men with metastatic, hormone-refractory prostate cancer prior to receiving chemotherapy and the results of the LATITUDE clinical trial suggest Zytig should be a new standard of care for men with newly diagnosed androgen sensitive prostate cancer.
Prostate cancer is a hormonally sensitive disease that can often be controlled for long periods with androgen-deprivation therapy (ADT). When prostate cancer stops responding to this treatment, it is referred to as hormone-refractory prostate cancer. Metastatic hormone-refractory prostate cancer is a challenging form of the disease to treat because the cancer has spread to distant sites in the body and does not respond to treatment with standard hormonal therapy.
Zytiga is an oral targeted agent that blocks the production of androgens (male hormones such as testosterone) not only by the testes, but also by the adrenal glands and the tumor itself. It was initially approved in April 2011 for use in patients whose prostate cancer progressed after chemotherapy.
The expanded approval was based on data from a study that involved 1,088 men with metastatic, hormone-refractory prostate cancer who had not previously received chemotherapy. Participants were randomized to receive Zytiga or placebo in combination with prednisone. Patients who received Zytiga had a median overall survival of 35.3 months compared with 30.1 months for those receiving the placebo.
The most common side effects of Zytiga included joint swelling or discomfort, low levels of potassium in the blood, fluid retention, muscle discomfort, hot flashes, diarrhea, urinary tract infection, cough, high blood pressure, heartbeat disorders, urinary frequency, increased nighttime urination, upset stomach or indigestion, and upper respiratory tract infection.
Zytiga’s expanded approval was part of the FDA’s priority review program, which allows an expedited six-month review of drugs that may offer major advances in treatment.
Zytiga Delays Metastatic Prostate Cancer Growth by 18 Months, Extends Survival in Men Previously Untreated With ADT
Adding Zytiga plus prednisone to standard hormonal therapy for men with newly diagnosed, metastatic prostate cancer lowers the chance of death by 38%, and more than doubled the median time until the cancer worsened, from 14.8 months to 33 months according to the results of a clinical study. The most recent update of the "LATITUDE" trial was published in Lancet Oncology - May 2019.(3)
About the LATITUDE Study
The LATITUDE clinical study evaluated 1199 men with newly diagnosed, high-risk metastatic prostate cancer who had not previously received ADT. All patients had at least two of three risk factors: Gleason score (a measure of tumor grade) of 8 or more, 3 or more bone metastases, or 3 or more visceral metastases (spread to other organs in certain areas of the body, such as the liver). Individuals were treated with ADT plus Zytiga and prednisone, or ADT alone and directly compared.
After a median follow-up of 51.8 months and a final analysis the overall survival has been confirmed to be significantly longer for patients receiving Zytig/ADT/prednisone. Zytig treated patients survived on average 53 months compared to 36.5 months for ADT alone.
Side effects attributable to Zytig include hypertension and hypokalemia.
The combination of Zytig plus prednisone with can now be considered standard of care in patients with high-risk CSPC.
Metastatic prostate cancer has been treated the same way for over 50 years until Taxotere (docetaxel) chemotherapy was shown to improve survival in 2015. Zytiga may be the next advance in treatment with the potential to further improve outcomes by combining it with Taxotere and studies are currently underway.
Neoadjuvant Zytiga Plus Hormonal Therapy Can Eliminate Tumor in Some Men with High-Risk Prostate Cancer
Six months of neoadjuvant treatment with the targeted agent Zytiga® plus hormonal therapy eliminated or nearly eliminated tumors in one-third of men with localized high-risk prostate cancer, according to the results of a study presented at the annual meeting of the American Society of Clinical Oncology (ASCO). The current study marks the first time that the drug has been investigated in earlier stages of prostate cancer and in the neoadjuvant (pre-surgical) setting.
Men with localized prostate cancer can often be cured with surgery or radiation alone; however, men with certain risk factors—such as a high Gleason score, very high PSA level, spread of cancer outside the prostate, and lymph node involvement—tend to have a high recurrence rate regardless of whether all detectable cancer is surgically removed and/or radiated. These men have what is referred to as localized high-risk prostate cancer (LHRPC). Men with LHRPC tend to have a poor prognosis—it is infrequently cured with radical prostatectomy (RP) and neoadjuvant hormonal therapy (androgen deprivation therapy, or ADT) has not been shown to improve outcomes.
The randomized phase II study included 56 men with LHRPC who were randomized to one of two groups. Group A included 27 men who received leuprolide hormonal therapy for 12 weeks followed by leuprolide plus Zytiga for another 12 weeks. Group B included 29 men who received Zytiga and leuprolide for the entire 24-week period. All men underwent prostate surgery after 24 weeks of therapy and the tissue was then examined for evidence of cancer.
Zytiga therapy was well tolerated by both groups. Among the men in group B (who received 24 weeks of Zytiga therapy), 34 percent experienced complete elimination of nearly complete elimination of their cancer prior to surgery. In group A, where the men received Zytiga therapy for half of the treatment period, 15 percent of men experienced complete or nearly complete elimination of their cancer.
These are significant results in a population of patients with a typically poor prognosis. The researchers concluded that the combination therapy could have the potential to improve outcomes for men with LHRPC. Further research is warranted to confirm these benefits.
Zytiga Approved for Prostate Cancer in 2011
The US FDA originally approved Zytiga™ for the treatment of advanced prostate cancer in 2011 based on a study that enrolled 1,195 men from 13 countries. The study participants had metastatic, hormone-refractory prostate cancer that has progressed after chemotherapy. Patients were treated with either Zytiga plus prednisone or prednisone alone. Zytiga improved overall survival by four months (overall survival was 15 months in the group that received Zytiga and 11 months in the group that did not receive Zytiga).
Zytiga Reduces Fatigue in Advanced Prostate Cancer
Zytiga® has been reported to reduce fatigue in addition to improving overall survival.
To assess how Zytiga affects fatigue—a common and potentially debilitating problem among men with advanced prostate cancer—researchers evaluated information from one of the Zytiga clinical trials. Information was available about 797 men who had been treated with Zytiga plus prednisone and 398 men who had been treated with prednisone alone. The two groups of men had similar fatigue scores at the start of the study.
- Fatigue was more likely to improve, and improved more quickly, among men treated with Zytiga.
Fatigue is a common problem among patients with advanced cancer and can have a profound effect on quality of life. The results of this analysis suggest that in addition to improving overall survival, Zytiga may also help to reduce fatigue among men with advanced prostate cancer.
Zytiga Prolongs Time to Pain Progression
The addition of Zytiga® to prednisone also significantly delays patient-reported pain progression and health-related quality-of-life deterioration compared with prednisone alone in chemotherapy-naive men with metastatic castration-resistant prostate cancer, according to the results of a study published in The Lancet Oncology.
In an international, double-blind trial, 1,088 patients with progressive, metastatic castration-resistant prostate cancer were randomly assigned to receive Zytiga plus prednisone or prednisone plus placebo in continuous 4-week cycles. Researchers measured patients’ pain (with the Brief Pain Inventory Short Form [BPI-SF] questionnaire) and health-related quality of life (HRQoL) (with the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire). The researchers then analyzed the data to evaluate clinically meaningful pain progression and deterioration in HRQoL.
At a median follow-up of 22.2 months, the median time to progression of mean pain intensity was significantly longer in patients receiving Zytiga/prednisone (26.7 months) than in those receiving prednisone/placebo (18.4 months). The median time to progression of pain interference with daily activities was also significantly longer in the Zytiga group—10.3 months compared to 7.4 months. What’s more, the median time to progression of worst pain intensity was also longer in the Zytiga/prednisone group (26.7 months) compared to the prednisone/placebo group (19.4 months), but the difference was considered non-significant.
The median time to HRQoL deterioration was longer in patients receiving Zytiga/prednisone (12.7 months) than in those receiving prednisone/placebo (8.3 months).
- Taplin ME, Montgomery RB, Logothetis C, et al. Effect of neoadjuvant abiraterone acetate (AA) plus leuprolide acetate (LHRHa) on PSA, pathological complete response (pCR), and near pCR in localized high-risk prostate cancer (LHRPC): Results of a randomized phase II study. Presented at the 2012 annual meeting of the American Society of Clinical Oncology, June 1-5, 2012, Chicago, IL. Abstract 4521.
- Ryan C, Smith M, Fizazi K, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. The Lancet Oncology. Volume 16, No. 2, p152–160, February 2015. updated Lancet Oncol. 2019 Apr 12. Epub ahead of print.
- Basch E, Autio K, Ryan CJ, et al: Abiraterone acetate plus prednisone versus prednisone alone in chemotherapy-naive men with metastatic castration-resistant prostate cancer: patient-reported outcome results of a randomized phase 3 trial. The Lancet Oncology. 2013; 14(12):1193-1199.
- de Bono JS, Logothetis CJ, Molina A et al. Abiraterone and increased survival in metastatic prostate cancer. New England Journal of Medicine. 2011;364:1995-2005.
- Sternberg CN, Scher HI, Molina A et al. Fatigue improvement/reduction with abiraterone acetate in patients with metastatic castration-resistant prostate cancer (mCRPC) post-docetaxel – results from the COU-AA-301 phase 3 study. Presented at the 2011 European Multidisciplinary Cancer Conference. Stockholm, Sweden. September 23-27, 2011. Abstract 7015.
- FDA news release. FDA approves Zytiga for late-stage prostate cancer. April 28, 2011.
- FDA expands Zytiga’s use for late-stage prostate cancer. [FDA News Release]. U.S. Food and Drug Administration website. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm331492.htm