The de novo metastatic prostate cancer global incidence is striking: 3% in the US and rising, 6% across Europe, 4-10% in Latin America, and nearly 60% in Asia-Pacific. Historically, ADT has been standard of care, however most men with metastases progress to mCRPC driven by the reactivation of AR signaling. As Dr. Fizazi notes, ADT + docetaxel is the new standard of care for men with metastatic hormone naïve disease (with high disease burden) based off of 3 recent RCTs: GETUG-15 , CHAARTED , and STAMPEDE . As Dr. Fizazi mentioned, the rationale for adding AA + prednisone to ADT for metastatic hormone-naïve prostate cancer patients is threefold: (i) the mechanism of resistance to ADT may develop early, (ii) ADT alone does not inhibit androgen synthesis by the adrenal glands or prostate cancer cells, and (iii) AA + prednisone improves overall survival (OS) in mCRPC patients and reduces tumor burden in high-risk, localized prostate cancer. These points suggest that there is a role for inhibiting extragonadal androgen synthesis prior to the development of castration resistance.
The objectives of LATITUDE were to evaluate the addition of AA + prednisone to ADT on clinical benefit in men with newly diagnosed, high-risk, metastatic hormone-naïve prostate cancer. High-risk was defined as meeting at least two of three criteria: (i) Gleason score ≥8, (ii) presence of ≥3 lesions on bone scan, (iii) presence of measurable visceral lesions. Patients were stratified by the presence of visceral disease (yes/no) and ECOG performance status (0, 1 vs 2) and then randomized 1:1 to either ADT + AA (1000 mg daily) + prednisone (5 mg) (n=597) or ADT + placebo (n=602). The co-primary endpoints were OS and radiographic progression-free survival (rPFS). Secondary endpoints included time to: (i) pain progression, (ii) PSA progression, (iii) next symptomatic skeletal event, (iv) chemotherapy, and (v) subsequent prostate cancer therapy. The study was conducted at 235 sites in 34 countries in Europe, Asia-Pacific, Latin America, and Canada. Dr. Fizazi notes that the study was designed and fully enrolled prior to publication of the CHAARTED  and STAMPEDED  results. For rPFS, with an alpha of 0.001 and power of 94%, 565 events (single analysis) were needed to detect an HR of 0.67. For OS, at an alpha of 0.049 and power of 85%, 426, 554, 852 (2 interim, 1 final analysis) events were needed to detect an HR of 0.81. The results presented today were from the first interim analysis.
The treatment arms were well balanced, with >95% of patients presenting with ≥3 bone metastases at screening in both arms. Over a median follow-up of 30.4 months, patients treated with ADT + AA + prednisone had a 38% risk reduction of death (HR 0.62, 95%CI 0.51-0.76) compared to ADT + placebo. Median OS was not yet reached in the ADT + AA + prednisone arm compared to 34.7 months in the ADT + placebo arm. OS rates at 3 years for the ADT + AA + prednisone arm was 66%, compared to 49% in the ADT + placebo arm. This OS benefit was consistently favorable across all subgroups including ECOG 0 and 1-2, visceral metastases, Gleason ≥8 disease, and bone lesions >10. Second, there was also 53% risk of reduction of radiographic progression or death for patients treated with ADT + AA + prednisone (median 33.0 months; HR 0.47, 95%CI 0.39-0.55) compared to ADT + placebo (14.8 months). Third, there was statistically significant improvement across all secondary endpoints for ADT + AA + prednisone: (i) time to PSA progression (HR 0.30, 95%CI 0.26-0.35), (ii) time to pain progression (HR 0.70, 95%CI 0.58-0.83), (iii) time to next symptomatic skeletal event (HR 0.70, 95%CI 0.54-0.92), (iv) time to chemotherapy (HR 0.44, 95%CI 0.35-0.56), and (v) and time to subsequent prostate cancer therapy (HR 0.42, 95%CI 0.35-0.50). Secondary to the above results, the study was discontinued after the first interim analysis. Adverse events were comparable in the two groups. Hypertension only rarely required treatment discontinuation, and only two patients discontinued treatment due to hypokalemia (no hypokalemia-related deaths). Two patients in each arm died of cerebrovascular events, and 10 patients treated with ADT + AA + prednisone compared to 6 patients treated with ADT + placebo died of cardiac disorders.
In conclusion, the phase III LATITUDE study demonstrated that ADT + AA + prednisone lead to a significantly improved OS with a 38% reduction in risk of death, significantly prolonged rPFS (53% reduction), and improvement across all secondary endpoints. The overall safety profile was consistent with the AA + prednisone mCRPC trials. Based on these findings, Dr. Fizazi states “the addition of AA + prednisone to ADT can potentially be considered a new standard of care for patients with high-risk, newly diagnosed hormone-naïve prostate cancer.” The full manuscript was subsequently published in the New England Journal of Medicine at the conclusion of today’s plenary session.
Presented by: Karim Fizazi, Gustave Roussy Cancer Campus and University Paris-Sud, Paris, France
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre
1. Gravis G, Fizazi K, Joly F, et al. Androgen Deprivation Therapy (ADT) alone or with Docetaxel in Non-castrate metastatic Prostate Cancer (GETUG-AFU 15): A randomized, open-label, phase 3 trial. Lancet Oncol: 2013 Feb;14(2):149-158.
2. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J Med 2015 Aug 20;373(8):737-746.
3. James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): Survival results from an adaptive, multiarm, multistage, platform randomized controlled trial. Lancet 2016;387(10024):1163-1177.
ASCO 2017 Abstract on LATITUDE
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