Metastatic castration-refractory prostate cancer (CR-PC) patients have poor prognosis with median survival of approximately 14 months. 10-20% of all prostate cancer patients develop metastatic CR-PC within 5 years of initial diagnosis, and therefore, improved therapeutic strategies are needed. Oligometastasis describes a clinical state where metastases are limited in number, and metastatectomies for various oligometastatic solid tumors can lead to long-term survival. Stereotactic Ablative Radiotherapy (SABR) is a noninvasive therapy with local control (LC) similar to surgery. In our experience, oligometastatic prostate cancer patients (65% were CR-PC) experienced 100% LC at 6 months with SABR with corresponding decline in their PSA. 11C-Choline PET/CT was FDA-approved in recurrent metastatic prostate cancer patients, and prior restaging studies have validated the sensitivity, specificity, positive predictive value, and negative predictive value of Choline PET at 85-100%, 76-96%, 76-91%, and 81-100%, respectively. Therefore, 11C- Choline PET/CT may help to identify true oligometastatic CR-PC patients. Objectives/Hypothesis: The combination of 11C-Choline PET/CT and SABR may improve true oligometastatic (CR-PC) patient selection, alter their clinical management (i.e., from noncurative to curative intent with the addition of SABR), and impact natural disease progression (improve LC, PSA progression-free survival and overall survival [OS]). SABR may also induce anti-prostate cancer immunity, which could be amplified into long-term protective immunity with immune-regulation inhibitors (e.g., ipilimumab, anti-PD1/PD-L1).
Specific Aims /Study Design: We propose a prospective single arm phase II clinical trial to assess the role of 11C-Choline PET/CT and SABR in metastatic CR-PC patients with the goal of improving clinical outcomes (Aim 1). We also propose a translational study in Aim 2 to explore the induction anti-prostate cancer immunity elicited by SABR treatments. The confirmation of the ability of SABR to induce anti-prostate cancer immunity would provide a robust rationale to combine SABR and immunomodulating agents (i.e., checkpoint inhibitors) in widespread castration- and chemotherapy- resistant metastatic prostate cancer. The proposed biomarker (CD11ahighPD-1high CD8+ T cells) may improve identification of potential responders to the combined SABR and anti-PD1 therapy. Impact: The incorporation of 11C-Choline PET/CT in the selection of oligometastatic CR-PC patients whose limited metastases are amenable to SABR may improve OS. If our hypothesis is proven successful, there would be a paradigm shift in the clinical management of these patients (i.e., from noncurative to curative intent). The in situ induction of anti-prostate immunity by SABR, if confirmed, would form a robust rationale for the combination of SABR and immunomodulating agents in future clinical trials.

Public Health Relevance

Metastatic prostate cancer patients whose disease is resistant to male testosterone inhibition therapy are described as having castration-refractory cancer. They have a poor survival prognosis of 14 to 17 months, and second-line therapies -- including chemotherapy -- do not lead to long-term survival. Therefore, improved treatment options are necessary to bolster their outcomes. In this application, Dr. Dong and I hope to combine our expertise in immunology and radiation therapy to accurately target and kill prostate cancer cells and thereby to prompt the patients' own immune cells to recognize the prostate cancer cells as foreign and to mount an immune attack. Prior research has shown that patients with a small number of metastatic lesions, referred to as 'oligometastases,' can benefit from aggressive surgical resection of all of the lesions and achieve long-term survivorship. A new imaging scan, known as 11C-Choline PET/CT, appears to detect metastatic cancer sooner than the currently available scans. The combination of 11C-Choline PET/CT scans and high-energy X-ray radiation treatments may therefore help in the selection of appropriate oligometastatic castration-refractory prostate cancer patients, who then can be treated with highly-focused radiation treatments and may experience improved clinical outcomes. Although a small percentage of oligometastatic patients may benefit from such aggressive treatment, the majority of these patients progress and succumb to their disease. The cancer cells grow because they are not recognized as foreign or because they shut down the immune response using various signals. Immunotherapy, on the other hand, uses the patient's own immune system to fight off cancer cells. High-dose X-rays cause inflammation, which draws immune cells to the radiated site so that they can engulf and process tumor antigens in order to activate an army of immune cells. Our hope and goal is to sustain this immune response against prostate cancer cells in the future by adding drugs that keep the immune system active by interfering with 'turn-off' signals. Successfully activating the immune system in prostate cancer patients with high-dose X-rays -- as demonstrated in animals and in humans with melanoma cancers -- would be a game-changing event in the fight against castration-refractory prostate cancer. The study of the patients' immune system requires blood draws before and after radiation treatments, and the associated risks are skin redness, bruising, and potential infection. The side effects of radiation treatments vary by the location of the treatment and will need further discussion with a radiation oncologist.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA200551-03
Application #
9414666
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Vikram, Bhadrasain
Project Start
2016-02-09
Project End
2019-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Parker, William P; Davis, Brian J; Park, Sean S et al. (2017) Identification of Site-specific Recurrence Following Primary Radiation Therapy for Prostate Cancer Using C-11 Choline Positron Emission Tomography/Computed Tomography: A Nomogram for Predicting Extrapelvic Disease. Eur Urol 71:340-348
Parker, William P; Evans, Jaden D; Stish, Bradley J et al. (2017) Patterns of Recurrence After Postprostatectomy Fossa Radiation Therapy Identified by C-11 Choline Positron Emission Tomography/Computed Tomography. Int J Radiat Oncol Biol Phys 97:526-535
Dronca, Roxana S; Mansfield, Aaron S; Park, Sean S et al. (2016) BCL-2-interacting mediator of cell death (Bim) is a novel biomarker for response to anti-PD-1 therapy in patients with advanced melanoma. Immunotherapy 8:1351-1353
Muldermans, Jonathan L; Romak, Lindsay B; Kwon, Eugene D et al. (2016) Stereotactic Body Radiation Therapy for Oligometastatic Prostate Cancer. Int J Radiat Oncol Biol Phys 95:696-702