William L. Dahut

The COVID-19 (coronavirus disease 2019) pandemic has worldwide implications on health care, especially in our most vulnerable population: cancer patients. Flexibility and adaptation are needed to continue clinical research and for clinical trial development. At the Intramural Research Program, National Cancer Institute, swift changes have been implemented to protect our patients while maintaining the scientific integrity of our cancer clinical trials. Many lessons have been learned including incorporation of telehealth into clinical trials, partnerships with the oncology community at both academic institutions and community practices, focusing on diversity and inclusion to improve scientific innovation, and strengthened relationships with regulatory agencies and institutional review boards. These changes will enhance the clinical trials we conduct well beyond the pandemic.

Traditionally, atherosclerotic risk factors for cardiovascular disease and cancer are assessed using coronary artery calcium scoring. However, this neglects the impact of atherosclerotic disease more proximal to the cancer site. This study assesses whether aortoiliac atherosclerotic plaque is associated with prostate cancer. The dataset consisted of abdominopelvic CT of 93 patients with prostate cancer and 186 asymptomatic patients who underwent CT colonography as an age- and gender-matched control group. Agatston scores were measured in the abdominal aorta, common iliac, and internal iliac arteries. The scores were evaluated for associations with age, Framingham risk score, and prostate cancer-related biomarkers, including prostate-specific antigen, Gleason score, tumor location, prostatectomy, androgen deprivation therapy, mortality, and bone metastasis. The atherosclerotic plaque of prostate cancer patients did not differ from the control group (p = 0.22) and was not correlated with any of the prostate cancer-related biomarkers (p > 0.05). However, Agatston scores of abdominal plaques correlated well with age (p < 0.001) and Framingham risk scores (p = 0.002).

Objective: To evaluate the safety and efficacy of cabozantinib combined with docetaxel. Patients and Methods: This was a phase 1/2 multicentre study in patients with metastatic castration‐resistant prostate cancer (mCRPC). Docetaxel (75 mg/m ² every 3 weeks with daily prednisone 10 mg) was combined with escalating doses of daily cabozantinib (20, 40 and 60 mg). Based on the results of the phase 1 study, the investigation was expanded into a randomized study of docetaxel with prednisone (hereafter 'docetaxel/prednisone') plus the maximum tolerated dose (MTD) of cabozantinib compared with docetaxel/prednisone alone. Results: A total of 44 men with mCRPC were enrolled in this phase 1/2 trial. An MTD of 40 mg cabozantinib plus docetaxel/prednisone was determined. Dose‐limiting toxicities were neutropenic fever and palmar‐plantar erythrodysesthesia, and there was one death attributable to a thromboembolic event. In addition, grade 3 or 4 myelosuppression, hypophosphataemia and neuropathy were seen in three or more patients. In the phase 1 study, the median time to progression (TTP) and overall survival (OS) time were 13.6 and 16.3 months, respectively. In the phase 2 study, which was terminated early because of poor accrual, the median TTP and OS favoured the combination ( n = 13) compared to docetaxel/prednisone alone ( n = 12; 21.0 vs 6.6 months; P = 0.035 and 23.8 vs 15.6 months; P = 0.072, respectively). Conclusion: Despite the limited number of patients in this study, preliminary data suggest that cabozantinib can be safely added to docetaxel/prednisone with possible enhanced efficacy.

Purpose: For high-risk prostate cancer, standard treatment options include radical prostatectomy (RP) or radiotherapy plus androgen deprivation therapy (ADT). Despite definitive therapy, many patients will have disease recurrence. Imaging has the potential to better define characteristics of response and resistance. In this study, we evaluated prostate multiparametric MRI (mpMRI) before and after neoadjuvant enzalutamide plus ADT. Patients and Methods: Men with localized intermediate- or high-risk prostate cancer underwent a baseline mpMRI and mpMRI-targeted biopsy followed by a second mpMRI after 6 months of enzalutamide and ADT prior to RP. Specimens were sectioned in the same plane as mpMRI using patient-specific 3D-printed molds to permit mpMRI-targeted biopsies to be compared with the same lesion from the RP. Specimens were analyzed for imaging and histologic correlates of response. Results: Of 39 patients enrolled, 36 completed imaging and RP. Most patients (92%) had high-risk disease. Fifty-eight lesions were detected on baseline mpMRI, of which 40 (69%) remained measurable at 6-month follow-up imaging. Fifty-five of 59 lesions (93%) demonstrated >50% volume reduction on posttreatment mpMRI. Three of 59 lesions (5%) demonstrated growth in size at follow-up imaging, with two lesions increasing more than 3-fold in volume. On whole-mount pathology, 15 patients demonstrated minimal residual disease (MRD) of <0.05 cc or pathologic complete response. Low initial mpMRI relative tumor burden was most predictive of MRD on final pathology. Conclusions: Low relative lesion volume at baseline mpMRI was predictive of pathologic response. A subset of patients had limited response. Selection of patients based on these metrics may improve outcomes in high-risk disease.

The novel coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is a global health threat (1). Patients with cancer are one of the most vulnerable populations. During this pandemic, clinical trial accrual to NCI studies has fallen dramatically. Investigators quickly turned to regulatory bodies to simplify treatment schedules, facilitate telemedicine, and decrease required data collection. Going forward, the oncology research community must use the lessons learned to focus on redesigning studies to ensure that critical scientific questions are answered safely while expanding access and increasing partnerships with community physicians. These changes will accelerate clinical progress while protecting our patients.

Background Checkpoint inhibitors have not been effective for prostate cancer as single agents. Durvalumab is a human IgG1-K monoclonal antibody that targets programmed death ligand 1 and is approved by the U.S. Food and Drug Administration for locally advanced or metastatic urothelial cancer and locally advanced, unresectable stage 3 non-small cell lung cancer. Olaparib, a poly (ADP-ribose) polymerase inhibitor, has demonstrated an improvement in median progression-free survival (PFS) in select patients with metastatic castration-resistant prostate cancer (mCRPC). Data from other trials suggest there may be improved activity in men with DNA damage repair (DDR) mutations treated with checkpoint inhibitors. This trial evaluated durvalumab and olaparib in patients with mCRPC with and without somatic or germline DDR mutations. Methods Eligible patients had received prior enzalutamide and/or abiraterone. Patients received durvalumab 1500 mg i.v. every 28 days and olaparib 300 mg tablets p.o. every 12 h until disease progression or unacceptable toxicity. All patients had biopsies of metastatic lesions with an evaluation for both germline and somatic mutations. Results Seventeen patients received durvalumab and olaparib. Nausea was the only nonhematologic grade 3 or 4 toxicity occurring in > 1 patient (2/17). No patients were taken off trial for toxicity. Median radiographic progression-free survival (rPFS) for all patients is 16.1 months (95% CI: 4.5–16.1 months) with a 12-month rPFS of 51.5% (95% CI: 25.7–72.3%). Activity is seen in patients with alterations in DDR genes, with a median rPFS of 16.1 months (95% CI: 7.8–18.1 months). Nine of 17 (53%) patients had a radiographic and/or PSA response. Patients with fewer peripheral myeloid-derived suppressor cells and with alterations in DDR genes were more likely to respond. Early changes in circulating tumor cell counts and in both innate and adaptive immune characteristics were associated with response. Conclusions Durvalumab plus olaparib has acceptable toxicity, and the combination demonstrates efficacy, particularly in men with DDR abnormalities. Trial registration ClinicalTrials.gov identifier: NCT02484404.

Prostate cancer is the most common solid tumor malignancy in men worldwide. Treatment with surgery and radiation can be curative in organ-confined disease. Unfortunately, about one third of men develop biochemically recurrent disease based only on rising prostate-specific antigen (PSA) in the absence of visible disease on conventional imaging. For these patients with biochemical recurrent prostate cancer, there is no uniform guideline for subsequent management. Based on available data, it seems prudent that biochemical recurrent prostate cancer should initially be evaluated for salvage radiation or prostatectomy, with curative intent. In selected cases, high-intensity focused ultrasound and cryotherapy may be considered in patients that meet very narrow criteria as defined by non-randomized trials. If salvage options are not practical or unsuccessful, androgen deprivation therapy (ADT) is a standard option for disease control. While some patients prefer ADT to manage the disease immediately, others defer treatment because of the associated toxicity. In the absence of definitive randomized data, patients may be followed using PSA doubling time as a trigger to initiate ADT. Based on retrospective data, a PSA doubling time of less than 3–6 months has been associated with near-term development of metastasis and thus could be used signal to initiate ADT. Once treatment is begun, patients and their providers can choose between an intermittent and continuous ADT strategy. The intermittent approach may limit side effects but in patients with metastatic disease studies could not exclude a 20% greater risk of death. In men with biochemical recurrence, large studies have shown that intermittent therapy is non-inferior to continuous therapy, thus making this a reasonable option. Since biochemically recurrent prostate cancer is defined by technological limitations of radiographic detection, as new imaging (i.e., PSMA) strategies are developed, it may alter how the disease is monitored and perhaps managed. Furthermore, patients have no symptoms related to their disease and thus many prefer options that minimize toxicity. For this reason, herbal agents and immunotherapy are under investigation as potential alternatives to ADT and its accompanying side effects. New therapeutic options combined with improved imaging to evaluate the disease may markedly change how biochemically recurrent prostate cancer is managed in the future.

Molecular imaging of prostate cancer is in a dynamic phase of development. Currently approved techniques are limited and researchers have been working on novel agents to improve accuracy in targeting and detecting prostate tumors. In addition, the complexity of various prostate cancer states also contributes to the challenges in evaluating suitable radiotracer candidates. We have highlighted nuclear medicine tracers that focus on mechanisms involved in bone metastasis, prostate cancer cell membrane synthesis, amino acid analogs, androgen analogs, and the prostate specific membrane antigen. Encouraging results with many of these innovative radiotracer compounds will not only advance diagnostic capabilities for prostate cancer but open opportunities for theranostic applications to treat this worldwide malignancy.