Optimizing Treatment of Prostate Cancer in Men living with HIV

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SUMMARY Cancer is a leading cause of morbidity and mortality among aging people with HIV (PWH) and prostate cancer is now one of the most common cancers among PWH. Despite this, prostate cancer remains the least studied tumor in terms of its natural history and clinical outcomes in the context of HIV. Our findings suggest that HIV infection is associated with rapid carcinogenesis, increased adverse treatment events, and elevated mortality risk. However, there are very limited data on the impact of HIV on treatment selection (versus active surveillance) on key short- and long-term outcomes, including cancer control, quality of life, and mortality particularly for PWH with clinically localized prostate cancer (the most commonly diagnosed stage). These include tradeoffs in toxicity profiles and oncologic control among therapeutic modalities, as well as competing risks of death from non-cancer causes. Quantifying the downstream harms and benefits of different management strategies for localized prostate cancers is critical to aid decision-making, maximize treatment benefits, and reduce harms. Despite compelling need, treatment of localized prostate cancer has never been investigated in the context of HIV in clinical trials, and extrapolating results from clinical trials in HIV uninfected persons is inappropriate due to differences in treatment complications and tolerability. Furthermore, unique HIV-related factors may substantially alter prostate cancer natural history, comorbidities, functional status, risk of second primary cancers, life expectancy, and quality of life. This project will determine the role of HIV on localized prostate cancer natural history and outcomes. We will synthesize a disease simulation that will be used to perform comparative assessment of common treatment pathways to guide treatment decision-making. Our Specific Aims are: (1) To evaluate the impact of immune dysfunction and specific ART regimens on a) active surveillance (AS) for low-risk disease, and definitive treatment for intermediate- and high-risk disease and b) outcomes and adverse treatment events for all stages of prostate cancer among PWH; (2) To create and validate a microsimulation model (HIv Prostate Treatment [HIPR-T]) of prostate cancer natural history and treatment outcomes for localized prostate cancer in PWH; and (3) To use the HIPR-T model to compare the benefits vs harms of optimized AS and definitive treatment for localized prostate cancer over the lifetime of PWH. To achieve these aims, we will use data from large, representative HIV/cancer cohorts (>3,000 PWH prostate cancer survivors) and a validated HIV natural history simulation framework. We will synthesize and validate a novel prostate cancer-HIV simulation model capturing AS, treatment initiation and definitive therapy outcomes. Then, we will use the enhanced model to assess the optimal management of PWH with localized prostate cancer that will maximize survival and quality of life. The findings from this study will transform the clinical decision-making process for early-stage prostate cancer, maximize benefits and reduce harms, reduce uncertainties and treatment disparities, and will inform treatment recommendations for managing prostate cancer among PWH.