Proefschrift

CHAPTER 7. DISCUSSION to therapy between the two therapy protocols. Availability of detailed information from blood serum markers, imaging techniques, and liquid biopsy could be used to identify the initial tumor composition at the time of initial treatment and can also be used serially to monitor the changes in tumor composition during treatment. These serial measures can provide feedback on the frequency dynamics simulated in combination with the PSA measurement and greatly improve the patient specific prediction for optimized therapy using model predictive control. 7.5 Clinical Perspectives While the success of the adaptive abiraterone therapy presented in Chapter 4 is a good start, patients receiving abiraterone have generally progressed through the list of other available drugs shown in Table 1.1. How long can overall survival be extended if adaptive therapy is used with every drug given? In order to address this question, two more additional clinical trials based on the mathematical modeling in this thesis have been opened. Firstly, an adaptive protocol is being tested for first line therapy of androgen deprivation therapy (ADT). ADT provides significant reduction of disease in patients presenting with metastatic prostate cancer. Unfortunately, relapse of disease to castrate-resistant prostate cancer occurs after an average of 13.9 months (Crawford et al., 1989). The Intermittent Androgen Deprivation Therapy for Stage IV Castration Sensitive Prostate Cancer (NCT03511196) trial uses the same adaptive protocol as the abiraterone adaptive therapy trial, dropping patient PSA by 50% before providing a drug holiday. If adaptive ADT at least doubles the time of drug effectiveness, like that of abiraterone, this could result in ADT providing at least 2.5 years of progression free survival, drastically delaying the progression to mCRPC and extending the overall survival of patients. Secondly, based on the work in this thesis, a multi-center pilot study to evaluate the clinical efficacy and evolutionary dynamics of adaptive enzalutamide in men with mCRPC is in preparation. Enzalutamide is a nonsteroidal antiandrogen that acts by directly blocking the effects of androgens, providing yet another tool to inhibit the prostate cancer cells from using androgen for continued growth. The median time to radiographic progression was 12.9 months for chemo-naive patients and 5.6 months for the post-chemotherapy patients (Higano et al., 2015). Again, if the simple adaptive protocol of cycling patients down to a 50% PSA measurement results in a doubling of time to progression, enzalutamide alone could provide over two years of survival. The serial combination of adaptive ADT, enzalutamide, and abiraterone could, in theory, extend progression free survival of prostate cancer patients to almost 10 years. Considering only 31.8% of patients using standard therapy survive to 5-year post diagnosis, the use of adaptive therapy has the potential to drastically change treatment success of mCRPC. The potential benefits of adaptive therapy should, in principle, not be limited to metastatic prostate cancer. In this light, there are two additional adaptive therapy trials based on the protocol from Chapter 4 in two additional cancers. A trial for adaptive tyrosine kinase inhibitor therapy in patients with thyroid cancer (NCT03630120) is recruiting 45 patients that can initially respond with a 50% drop in tumor marker level 114