As reported in the Journal of Clinical Oncology by Chi et al1—and summarized in this issue of The ASCO Post—the prespecified final overall survival analysis of the phase III TITAN trial1-3 has confirmed a clear overall survival and radiographic progression-free survival benefit with the combination of apalutamide and androgen-deprivation therapy vs placebo plus androgen-deprivation therapy in patients with metastatic castration-sensitive prostate cancer. The trial showed an overall survival benefit of the combination, both with and without adjustment for the large crossover from placebo to apalutamide. The trial also showed that the combination significantly delayed the time to prostate-specific antigen disease progression and the time to cytotoxic chemotherapy, improved second progression-free survival, and delayed the time to evolution of castration resistance. The aforementioned clinically relevant results were accomplished without substantial changes from baseline in health-related quality of life (overall or in specific domains) on the Functional Assessment of Cancer Therapy–Prostate assessment. Of note, no new safety signals or changes in adverse-event profile were observed compared with the previously reported adverse event and safety profile from the phase III SPARTAN trial,4 which led to the approval of apalutamide for patients with nonmetastatic castration-resistant prostate cancer.
The TITAN investigators should be congratulated for the detail and breadth of their adverse-event reporting as well as the robust duration of long-term follow-up for both overall and second progression-free survival. Given the highest level of evidence now unequivocally demonstrated by the TITAN trial results, it is absolutely clear that patients with metastatic castration-sensitive prostate cancer who have low- or high-volume disease and de novo or recurrent metastatic castration-sensitive disease at diagnosis are best served by combination therapy, inclusive of androgen-deprivation therapy and an androgen receptor (AR) inhibitor. Other important phase III trials (LATITUDE,5 STAMPEDE,6 ARCHES,7 ENZAMET8) have certainly established the roles for both abiraterone acetate and enzalutamide for these same patient populations with metastatic castration-sensitive prostate cancer.
Why are approximately 50% of newly diagnosed patients [with metastatic castration-sensitive prostate cancer] in the United States receiving androgen-deprivation therapy alone?— Neal D. Shore, MD, FACS
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Unanswered Questions
Nonetheless, several questions remain. First, and most importantly, why are approximately 50% of newly diagnosed patients in the United States receiving androgen-deprivation therapy alone?9
Second, what is the impact of prior taxane-based chemotherapy? Prior chemotherapy (nonrandomized) was received by approximately 11% of patients in the TITAN and by approximately 18% of patients in the ARCHES study, with forest plot analyses suggesting a benefit of combination androgen-deprivation therapy and AR antagonist therapy with prior chemotherapy use; randomized prospective trials are needed to investigate the impact of prior chemotherapy use. Similarly, concomitant triplet therapy (androgen-deprivation therapy with chemotherapy and an AR antagonist) still requires evidence-based assessment.
Third, if androgen-deprivation therapy plus docetaxel is administered in combination per CHAARTED10 and STAMPEDE6, is there a role for sequencing an AR antagonist prior to the development of castration-resistant prostate cancer?
Fourth, since the highest-level evidence is lacking for use of vintage AR antagonists (bicalutamide, flutamide, nilutamide) with androgen-deprivation therapy for patients with metastatic castration-sensitive prostate cancer in comparison to the novel hormonal agents (abiraterone acetate, enzalutamide, apalutamide), what are the explanations for the ongoing clinician prescribing behavior? Presumably, the answers include matters of accessibility—eg, financial cost via payer barriers and differences in regulatory approvals in different regions of the world. Continuing education and sharing of the highest level of evidence and international guideline recommendations (eg, from ASCO, ESMO, and NCCN) for combination therapy, as well as appreciation for results of well-conducted trials such as TITAN, are of paramount importance for optimizing the care of patients with advanced prostate cancer.
Dr. Shore is employed by GenesisCare US, Carolina Urologic Research Center, Myrtle Beach, South Carolina.
DISCLOSURE: Dr. Shore has served as a consultant or advisor to AbbVie, Amgen, Astellas Pharma, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb/Sanofi, Clovis Oncology, Cold Genesys, Dendreon, Exact Imaging, Exact Sciences, FerGene, Ferring, Foundation Medicine, CG Ooncology, Genesis Care, Genzyme, InVitae, Janssen Scientific Affairs, MDxHealth, Medivation/Astellas, Merck, Myovant Sciences, Myriad Genetics, Nymox, Pacific Edge Biotechnology, Pfizer, Phosphorus, Propella Therapeutics, Sanofi, Sesen Bio, Tolmar, and Urogen Pharma; has participated in a speakers bureau for Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, Dendreon, Guardant Health, Janssen, and Pfizer; and has received research funding from AbbVie, Amgen, Astellas Pharma, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb/Pfizer, Clovis Oncology, Dendreon, Exact Imaging, Ferring, Foundation Medicine, InVitae, Janssen, MDxHealth, Merck, Myovant Sciences, Myriad Genetics, Nymox, Pfizer, Sanofi, Sesen Bio, and Tolmar.
REFERENCES
1. Chi KM, Chowdhury S, Bjartell A, et al: Apalutamide in patients with metastatic castration-sensitive prostate cancer: Final survival analysis of the randomized, double-blind, phase III TITAN study. J Clin Oncol 39:2294-2303, 2021.
2. Chi KN, Agarwal N, Bjartell A, et al: Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med 381:13-24, 2019.
3. Agarwal N, McQuarrie K, Bjartell A, et al: Health-related quality of life after apalutamide treatment in patients with metastatic castration-sensitive prostate cancer (TITAN): A randomised, placebo-controlled, phase 3 study. Lancet Oncol 20:1518-1530, 2019.
4. Smith MR, Saad F, Chowdhury S, et al: Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med 378:1408-1418, 2018.
5. Fizazi K, Tran NP, Fein L, et al: Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med 377:352-360, 2017.
6. James ND, de Bono JS, Spears MR, et al: Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med 377:338-351, 2017.
7. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al: ARCHES: A randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol 37:2974-2986, 2019.
8. Davis ID, Martin AJ, Stockler MR, et al: Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med 381:121-131, 2019.
9. George DJ, Agarwal N, Rider JR, et al: Real-world treatment patterns among patients diagnosed with metastatic castration-sensitive prostate cancer in community oncology settings. 2021 ASCO Annual Meeting. Abstract 5074. Presented June 4, 2021.
10. Sweeney CJ, Chen YH, Carducci M, et al: Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 2015; 373:737-746, 2015.
