Chemoimmunotherapy for Aggressive Variant Prostate Cancers (AVPC)
Abstract
The aggressive variant prostate cancers (AVPC) are a subset of prostate cancers that respond poorly to standard therapies for prostate cancer and markedly worsen the quantity and the quality of life of afflicted patients. We have shown that men with AVPC do better with a combination of cabazitaxel plus carboplatin than with cabazitaxel alone. However, all of the patients ultimately progress, so there is an urgent need to develop more effective therapies for men with AVPC who remain with a very poor prognosis and limited treatment options. We are conducting a randomized clinical trial to ask whether the drug olaparib given as maintenance therapy after treatment with six cycles of cabazitaxel plus carboplatin chemotherapy can prolong the duration of response in men with AVPC. Our early experience indicates that the addition of olaparib maintenance after induction treatment with cabazitaxel plus carboplatin will indeed be of marked benefit to men with AVPC. Nonetheless, some of the men with AVPC have disease progression before completing six cycles of chemotherapy, and it is expected that all will eventually progress despite olaparib maintenance. Recent clinical trials have shown that the addition of immunotherapies such as the drug durvalumab can significantly improve the efficacy of chemotherapy agents and olaparib. This was true in cancers that are similar to AVPC in their aggressive clinical behavior and response to chemotherapy combinations that contain carboplatin, like the small-cell lung cancers and the triple negative breast cancers. The combinations of these drugs appeared to be safe and tolerable. Therefore, we propose that the addition of durvalumab to cabazitaxel plus carboplatin induction and olaparib maintenance will help men with AVPC live better and longer, and we propose a clinical trial to test this hypothesis. However, it is likely that not all men with AVPC will benefit from such a combination and that even those who do will not be cured by it. In order to enable further advances and arrive at curative therapies, we must understand what the mechanisms of response and resistance are to the combinations of drugs that we administer and also find new targets for novel therapies. While animal models can shed some light on these mechanisms, they fail to reflect the complexity and heterogeneity of the human disease. Therefore, tumor biopsies are needed to gain the necessary knowledge that will inform the rational, biologically based design of improved therapeutic combinations and/or sequences to cure the AVPC. In this study, we will use cutting-edge technologies to analyze tumor biopsies obtained from clinical trial participants in order to understand how the addition of durvalumab to cabazitaxel plus carboplatin and to olaparib affects the immune response in the tumor. We will learn whether durvalumab is the optimal therapy to add to these agents or other immunotherapies should be considered for some or all of the patients. In this way, we are addressing the FY19 PCRP Overarching Challenges to “develop treatments that improve outcomes for men with lethal prostate cancer” and “define the biology of lethal prostate cancer to reduce death.” It is expected that the knowledge gained from our studies will markedly change the outcome for men with AVPC within the next 5 years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010257
Entities
People
- Ana Aparicio
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army