102 Background: For patients who have a rising prostate-specific antigen value after definitive local therapy, androgen deprivation is a commonly employed option. However, immediate hormonal therapy has not been shown to alter the progression of the disease. Prior studies showed the dependence of early tumor growth and progression on anaerobic metabolism through glycolysis. Autophagy is conserved, genetically controlled catabolic response to starvation and stress whereby cells self-digest intracellular proteins and organelles by targeting them for degradation in lysosomes to generate energy and mitigate damage, thereby supporting cancer cell survival. Our hypothesis was that the autophagic inhibitor, hydroxychloroquine, when utilized in prostate cancer, would interfere with defective autophagy such that tumor growth will be slowed or stopped. Methods: Patients had rising PSA after primary therapy for PC, no radiographic evidence of metastasis, no (neo)adjuvant ADT within 3 months of enrollment and testosterone > 150 ng/dL. Hydroxychloroquine was dosed at 400 mg/day (cohort 1) or 600 mg/day (cohort 2). Endpoints were PSA response (change in slope of PSA rise by at least 25%, when log (PSA) is plotted vs. time). Results: 64 patients (36 cohort 1; 28 patients cohort 2) with median age 71(55-94) and baseline PSA was 3.25ng/ml (0.24- 45.69ng/ml) were enrolled in the study. 39 patients completed 6 months of hydroxychloroquine therapy and 44 patients completed 5 months of treatment. Out of 64 patients, 52 had at least 5 PSA measurements after the start of treatment, and we restrict our analysis to these patients. In 33 patients of these 52 (63%), the doubling time decreased after treatment began. In 12 of these 52 (23%), the “doubling time” turned negative, consistent with decreasing PSA value. Most common adverse events were diarrhea (26%), nausea (12%) and rash (12%). Conclusions: Hydroxychloroquine appears to have some activity in PSA progression after localized therapy with minimal toxicity. Given that hydroxychloroquine has limited side effects, this drug has the potential to augment responses to hormonal therapy or chemotherapy. Clinical trial information: NCT00726596.
Prostate-Specific Antigen Nadir and Time to Prostate-Specific Antigen Nadir Following Maximal Androgen Blockade Independently Predict Prognosis in Patients with Metastatic Prostate Cancer