Prostate cancer patients are at increased risk of poor outcomes from COVID-19 infection, and so should be prioritized for vaccination (see figure).

Figure 1. Potential reasons for COVID-19 vaccine prioritization in patients with prostate cancer. Androgen and androgen receptor signaling axis drives expression of TMPRSS2, a membrane protease involved in the early steps of SARS-CoV-2 infection. Immunosuppressive effects of androgens can result in poor innate immune response and severe inflammatory response. Common factors that increase severity of prostate cancer and COVID-19 include comorbidities and behavioral factors. Severe inflammation resulting from COVID-19 can accelerate clinical progression of prostate cancer. (Created under paid subscription with Biorender.com.)

COVID-19 disproportionately affects older men, with a reported 58% to 60% of cases in males.¹ Morbidity and mortality from COVID-19 are significantly higher in older patients (36% vs 15% in those ≥64 years).² Emerging data suggest that patients with cancer also have a higher risk of severe clinical events than those without cancer. The data suggesting that cancer is an isolated risk factor for poorer COVID-19 outcomes are compelling. A recent meta-analysis of 28 cohorts of patients with prostate cancer who are COVID-19 positive reports that patients with cancer had a greater risk of disease severity and mortality from COVID-19.³ Several retrospective studies have shown that cancer patients infected with SARS-CoV-2 have higher rates of morbidity and mortality.^1,4,5 Zhang et al performed a systematic review and meta-analysis of 3,019 patients with cancer and COVID-19 from 15 studies across the UK, Europe, USA, Canada and Asia.⁶ Here again, poorer outcomes of COVID-19 were confirmed in cancer patients than in noncancer patients, and the study highlighted both age and gender as significant risk factors. An overriding theme in the literature is the higher risk for older male patients with comorbidities. Based on these demographics alone, prostate cancer patients should be a priority for COVID-19 vaccination.

The angiotensin-converting-enzyme 2 receptor (ACE2) and the transmembrane protease serine 2 (TMPRSS2) are essential host factors for successful SARS-CoV-2 infection. The virus spike glycoprotein (S) is a critical determinant of tropism and pathogenesis, and the interaction between S protein and host ACE2 mediates the first step in the infection cycle. The virus’s entry into the cell is achieved by proteolytic cleavage of the S protein by TMPRSS2. TMPRSS2, an androgen receptor-regulated gene, is abundantly expressed in prostate epithelial cells, and prostate adenocarcinoma has the highest TMPRSS2 expression of all cancers. A minor percentage of the prostate club and hillock epithelial express both ACE-2 and TMPRSS2. Therefore, spread of SARS-CoV-2 to the prostate is theoretically possible owing to the expression of ACE2 and TMPRSS2. The pathogenesis of SARS-CoV2 is associated with severe systemic inflammation with elevated levels of pro-inflammatory cytokines, including IL-1, IL-6, IL-8 and TNF. Interestingly, our ongoing studies show that these same cytokines are also associated with prostate cancer progression (manuscript in preparation). While it has not been determined if men diagnosed with prostate cancer specifically are at higher risk of COVID-19 related morbidity or mortality, the intersection of gender, TMPRSS2 and the possible impact of inflammatory cytokines warrants further study.

Underlying Malignancy vs the Comorbid State and the Predisposition of Prostate Cancer Patients to COVID-19 Severity

COVID-19 and prostate cancer share many risk factors, including demographic and socioeconomic factors, comorbidities and androgen signaling as a pathway in pathogenesis.¹ A number of studies have highlighted racial and ethnic disparities in COVID-19, with the highest rates of infection and death among Latinos and African Americans, a pattern similar to that seen in prostate cancer incidence and mortality.

Comorbidities such as diabetes, cardiovascular disease and obesity are known risk factors for prostate cancer and are also associated with worse outcomes in COVID-19 patients. Previous studies have established sex based differences in the incidence of each of these comorbidities, all of which are more common in men than in women diagnosed with SARS-CoV-2.¹ Obesity and other proinflammatory conditions are known to induce ACE2 and TMPRSS gene expression. A study in the Mount Sinai Health System reported that 6% of patients who were COVID-19 positive had breast, prostate, lung, urothelial and/or colon cancer, with a significantly higher intubation rate compared to patients without cancer.⁷ Several recent studies have also reported increased incidence of COVID-19 in patients with prostate cancer compared to other genitourinary (GU) cancers.^4,5,8,9 Our data further show that prostate cancer patients had a significantly higher intubation rate (25.4%) than male patients who were COVID positive with GU cancers other than prostate (21.3%, p=0.02). Patients with prostate cancer who were COVID-19 positive had a higher mortality rate compared to all male patients in the study with a history of other malignancies at 23.7% (27) vs 12.7% (43; p <0.01).¹

Anti-Androgens May Play a Role in a Multipronged Approach to Reduce COVID-19 Infection and Severity

Androgens control cellular activity and androgen receptor (AR) functions. Recent studies demonstrate that both TMPRSS2 and ACE2, the critical proteins in COVID-19 infection, may be under AR transcriptional control. Androgens and androgen receptors directly influence the extent of the immune response following viral infections, although the immune suppressive effects of androgens on immune cell subsets are not well known. This is also in line with the previous observation that men of African ancestry are more likely to have more significant AR dysregulation, contributing to the racial disparities seen in COVID-19. Androgens contribute to lower antibody titer levels in males than in females after viral infection by affecting B lymphopoiesis. Therefore, anti-androgens have the potential to significantly reduce the magnitude and severity of SARS-CoV-2 infection by blocking the immune suppressive effects of androgens and by lowering TMPRSS2 levels.

Androgen-driven immune modulation may also contribute to differences in clinical outcomes. Androgens generally have an immune suppressive effect, while gonadal testosterone deprivation has an immune stimulatory effect. This is supported by recent publications reporting that those treated with anti-androgens for prostate cancer demonstrated lower rates of SARS-CoV-2 infection and complications than those who did not receive ADT.⁸ Our group’s work shows that men with a diagnosis of prostate cancer have a higher risk of infection and death than similarly aged men with other cancers, none of whom are expected to be using ADT. This suggests that other important factors contribute to the differences in SARS-CoV-2 diagnosis and death from COVID-19 rather than androgen-mediated events such as viral entry or immune modulation alone. Prospective trials to definitively address the role of androgen in COVID-19 are ongoing, and these studies highlight the need for a personalized, risk-stratified approach to the use of androgen-targeting therapies for COVID-19.

In summary, patients with prostate cancer are speculated to have a weakened immune system, which is further compounded by the immunosuppressive role of androgens, and they are more vulnerable to COVID-19 infection. Affected individuals show increased disease severity and mortality. To mitigate the unprecedented effects of COVID-19 on patients with prostate cancer, we believe that early vaccination is critical for these patients. Urologists and radiation oncologists, GU oncologists and the urology research community can play a leading role in the response to the COVID-19 pandemic by contributing both to frontline care and advocating for vaccination for their patients.

Acknowledgment

This work was supported by The Arthur M. Blank Family Foundation.