AUA 2019: Second Opinion Cases (Ask the Guidelines!): Castration Resistant Prostate Cancer
Case 1: Oliogometastatic Hormone Sensitive Prostate Cancer
Ironically for a session nominally focused on castrate-resistant disease, the first case involved a 72-year-old man with hormone-naive prostate cancer metastatic to only 3 small sites in the bone. The relevance to castrate resistant disease quickly became clear, however, as Dr. Cookson and Dr. Oh described the results of the CHAARTED, LATITUDE, and ARCHES trials. These trials respectively demonstrated improved overall survival with the addition of 6 cycles of docetaxel, continuous abiraterone, and continuous enzalutamide - drugs previously restricted to the castrate-resistant space - to standard androgen deprivation (ADT). Considerations for which of these agents to use first were discussed. In CHAARTED, the benefit of docetaxel was seen almost entirely in the pre-planned subgroup analysis of men with higher volume metastatic disease. Abiraterone did not have this limitation, but must be given continuously rather than over a limited period of time like docetaxel. Finally, the ARCHES trial demonstrated the utility of enzalutamide in this context, however it was only recently reported at the American Society of Clinical Oncologists meeting in 2019 and the final published manuscript and FDA approval have yet to arrive.
Dr. Lowrance and Dr. Oh also discussed maintenance of bone health in these patients, including regular DEXA scans, calcium and vitamin D supplementation, and administration of denosumab or zoledronic acid if indicated. Dr. Oh expressed a preference for denosumab in part because it can be given as a subcutaneous injection rather than a 15-minute infusion.
Discussion of this case concluded with a brief mention of three trials, TRoMbone, G-RAMPP, and SWOG 1802, which are ongoing and will seek to elucidate the role of radical prostatectomy in oligometastatic disease.
Case 2: Asymptomatic, Non-metastatic Castrate-Resistant Prostate Cancer
Discussion of this case began with Dr. Lowrance emphasizing the definition of castrate resistance, which requires a rise in PSA in spite of castrate levels of serum testosterone which must be confirmed at least 3 weeks later with a repeat measurement.
Similar to the previous case scenario, further discussion centered on three recent landmark trials in this population, PROSPER, SPARTAN, and ARAMIS. Each of these studies recruited men with castrate-resistant prostate cancer, no evidence of metastatic disease, and a PSA doubling time of less than ten months. Each showed a significant increase in median overall survival of at least 18 months for enzalutamide, apalutamide, and darolutamide respectively. Each of these is FDA approved for this indication except for darolutamide, the approval of which is pending despite the trial data being already published in the New England Journal of Medicine in early 2019.
The role of advanced imaging, such as PSMA PET was also briefly considered, and it is interesting to wonder how the results of these M0 CRPC trials will be applied in the era of significantly increased detection of previously occult metastatic disease, although the panel could offer little guidance in the interpretation of these studies at the present time.
Case 3: Metastatic castrate resistant prostate cancer
The session ended with a discussion of the most common presentation of castrate-resistant disease, a man with moderate volume of metastatic disease whose PSA has begun to rise while he is on ADT. In this case, the patient is beginning to experience significant pain causing him to request opioid medications.
Dr. Lowrance started by mentioning the enthusiasm for immunotherapy in other cancers, however, this patient’s significant bone pain makes him ineligible for sipuleucel T, the only FDA-approved immunotherapy for metastatic prostate cancer.
Dr. Oh then discussed the next best therapy for this patient. Since in this scenario the patient had already been given abiraterone with his initial ADT, in keeping with LATITUDE as discussed above, Dr. Oh cited his own work published in Clinical Genitourinary Cancer in 2017 to support adding an agent such as docetaxel or radium 223 which do not directly target the androgen synthesis and receptor pathway. Dr. Cookson emphasized the frequency with which DNA repair mutations are discovered in these patients, 23% total and 11.8% germline. Genetic testing of the germline and primary may help guide therapy, as these mutations are associated with significantly increased response to the PARP inhibitor olaparib. Similarly, BRCA2 mutations predict response to carboplatin and taxanes.
Given the pace of change in this field, it is a virtual certainty that at least some of the recommendations in this session will change by the start of next year’s AUA, however this thorough and concise application of the guidelines to realistic clinical scenarios was a much-appreciated review of the landscape as it stands today.
Moderated by: David Jarrard, MD, University of Wisconsin
Panelists: William Lowrance, MD, University of Utah, Huntsman Cancer Institute, Michael Cookson, MD, MMHC, Professor and Chair, University of Oklahoma
Written by: William Oh, MD, Icahn School of Medicine at Mount Sinai at the American Urological Association's 2019 Annual Meeting (AUA 2019), May 3 – 6, 2019 in Chicago, Illinois