Redefining the Clinical States of Prostate Cancer in the Modern Era
Rana R. McKay, MD, reflects on a proposal from her colleagues regarding a new model for guiding the treatment of prostate cancer that focuses on a “transitional” disease state.
McKay is from the University of California San Diego, Moores Cancer Center, La Jolla, CA
The authors of the accompanying article present a call to action to redefine historically characterized prostate cancer disease states to a contemporary model that emphasizes earlier interventions to prevent disease progression. They propose recategorization of prostate cancer into 4 states: localized, biochemically recurrent, transitional, and advanced disease. In the proposed model, biochemically recurrent disease would encompass castration-sensitive prostate cancer, including both states of rising prostate-specific antigen alone and oligometastatic disease. Transitional disease would include patients with de novo oligometastatic disease, metastatic castration-sensitive, nonmetastatic castration-resistant, and advanced disease representing the former lethal state of metastatic castration-resistant prostate cancer. The model emphasizes the integration of next-generation imaging, biomarkers, and earlier interventions to prevent the progression to advanced disease.
Accurate staging and disease detection of localized, biochemically recurrent, and metastatic prostate cancer is of critical importance to optimizing local and systemic treatment. Next-generation imaging, including positron emission tomography (PET) and multiparametric magnetic resonance imaging (mpMRI), have emerged as more advanced techniques for prostate cancer localization. The FDA approval of Ga 68 PSMA-11 PET in December 2020 in the United States is a landmark event for the widespread availability of this imaging modality for men with prostate cancer. While this is an overall advancement for patients with prostate cancer, many questions exist regarding the management of oligometastatic disease detected on next-generation imaging and the role of local treatment, metastasis-directed therapy, and systemic therapy in this context. Ultimately, we need robust data derived from well-designed, prospective clinical trials to optimize the utilization of next-generation imaging techniques and validate whether the augmentation of clinical practice based on imaging improves patient outcomes. Furthermore, newer imaging modalities are not yet widely accessible. Pending further validation to clarify usage in routine practice, steps need to be taken to ensure broad and equal access among men with prostate cancer.
Advances in molecular technologies have enabled large-scale genomic analyses of metastatic prostate cancer. These advancements have revealed a high frequency of alterations in cancer-specific genes that are actionable or being investigated as candidate predictive biomarkers to guide therapy selection for patients with advanced disease. The approval of PARP inhibitors for patients with metastatic castration-resistant prostate cancer has launched us into the era of precision medicine.1,2 The identification of numerous potentially actionable alterations have fueled biomarker-based clinical trials of novel therapeutics, as well as standard therapies. As we move forward, it is critical that such studies are designed across the spectrum of the disease’s natural history to prevent the emergence of castration resistance and disease progression.
Lastly, the authors emphasize the early intervention of antiandrogens in the management of prostate cancer, based on a series of phase 3 studies in men with nonmetastatic castration-resistant prostate cancer and metastatic hormone-sensitive prostate cancer. In addition to the early use of antiandrogens, several large phase 3 studies have demonstrated the utility of early chemotherapy with docetaxel3,4 and abiraterone.5,6 Currently, there are no prospective studies comparing choice of agent among docetaxel, abiraterone, and next-generation antiandrogens. Biomarker-based strategies will be critical to optimize therapy intensification and de-escalation strategies. Additionally, defining early intermediary end points such as metastasis-free survival, a robust surrogate for overall survival in prostate cancer, will enable the earlier integration of therapeutic interventions for men with localized or biochemically recurrent disease.
The authors should be commended for proposing a change in the former categorization of prostate cancer disease states to better reflect current advancements in imaging and genomics. However, in its current form, the taxonomy is somewhat ambiguous and does not reflect the underlying biology or a regulatory framework for drug development and approval. There is a need to build on the existing framework established by the Prostate Cancer Working Groups 2 and 3, which links disease biology to drug development and common clinical practice.7,8 Subsequent guidelines addressing the full spectrum of the natural history of prostate cancer and integrating advancements in imaging and biomarkers will be warranted, to optimize future clinical trial design and the clinical care of patients with prostate cancer.
FINANCIAL DISCLOSURE: McKay reports research funding from Bayer, Pfizer, Tempus; serves on Advisory Board for AstraZeneca, Bayer, Bristol Myers Squibb, Calithera, Exelixis, Janssen, Merck, Novartis, Pfizer, Sanofi, Tempus; is a consultant for Dendreon, Vividion; and serves on the molecular tumor board at Caris.
References
1. Abida W, Patnaik A, Campbell D, et al; TRITON investigators. Rucaparib in men with metastatic castration-resistant prostate cancer harboring a BRCA1 or BRCA2 gene alteration. J Clin Oncol. 2020;38(32):3763-3772. doi:10.1200/JCO.20.01035
2. de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020;382(22):2091-2102. doi:10.1056/NEJMoa1911440
3. James ND, Sydes MR, Clarke NW, et al; STAMPEDE investigators. 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 randomised controlled trial. Lancet. 2016;387(10024):1163-1177 doi:10.1016/S0140-6736(15)01037-5
4. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373(8):737-746. doi:10.1056/NEJMoa1503747
5. Fizazi K, Chi KN. Abiraterone in metastatic prostate cancer. N Engl J Med. 2017;377(17):1697-1698. doi:10.1056/NEJMc1711029
6. James ND, Spears MR, Sydes MR. Abiraterone in metastatic prostate cancer. N Engl J Med. 2017;377(17):1696-1697. doi:10.1056/NEJMc1711029
7. Scher HI, Halabi S, Tannock I, et al; Prostate Cancer Clinical Trials Working Group. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008;26(7):1148-1159. doi:10.1200/JCO.2007.12.4487
8. Scher HI, Morris MJ, Stadler WM, et al; Prostate Cancer Clinical Trials Working Group 3. 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(12):1402-1418. doi:10.1200/JCO.2015.64.2702
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