Hydroxychloroquine effects on tumor suppressor PAR-4 levels in patients with oligometastatic prostate cancer: Results from a phase-2 trial.

233 Background: In oligometastatic prostate cancer (OMPC), delaying time to initiation of androgen deprivation therapy (ADT) may have oncologic and quality of life benefits. Additionally, there is an emerging role for metastatic/primary tumor site-directed therapy for patients with OMPC. Prostate apoptosis response-4 (PAR-4) is a potent tumor suppressor, facilitating apoptosis in prostate cancer cells. Hydroxychloroquine (HCQ) has been identified to be a potent inducer of PAR-4 secretion and downstream tumor inhibition in preclinical models and Phase I trials. We present a single institution Phase II trial assessing induction of PAR-4 levels in the plasma of patients in response to HCQ administration in combination with radiation therapy (RT) for OMPC. Methods: Men with OMPC (≤5 synchronous metastatic lesions) following primary tumor treatment were eligible. Patients received 400 mg HCQ daily for 2 weeks prior to metastatic site-directed RT and 400 mg HCQ daily for 90 days post-radiation. Plasma samples were collected on Day 0, 14, 30, 60, and 90. The primary endpoint was induction of ≥50% serum PAR-4 expression above baseline level within 90 days of treatment initiation. We hypothesized that over half of patients would exhibit ≥50% induction of serum PAR-4 expression. Results: Nineteen participants met inclusion criteria and were treated with 90 days of HCQ and RT to oligometastatic lesions. Median age was 68 years (range 55-77), the majority of patients were Caucasian (94%) and the median baseline PSA was 6.30 ng/ml (range 0.99 to 27.80). Prior primary tumor treatment included radiation therapy in 26%, radical prostatectomy in 32%, and radical prostatectomy with radiation in 42%. Eleven patients (58%) showed ≥50% increase in plasma PAR-4 above baseline levels (p=0.0006). This was associated with a concomitant PSA decline at 6-months (mean -0.98 ng/ml, 95% CI -6.61 to 4.65) and 12-months (mean -7.21 ng/ml, 95% CI -12.45 to -1.97). At 12-month follow-up, seven patients (37%) were free from ADT and median progression-free survival was 9.3 months (95% CI 6.4 to N/A). Twelve patients (63%) reported at least one adverse event, with 2 patients (11%) experiencing grade 3 toxicity. Conclusions: Oral administration of HCQ is well tolerated and effectively induces plasma expression of the potent tumor suppressor PAR-4 in patients with OMPC. Given the promising findings, further investigation into possible radiosensitizing and anti-tumor benefits of HQC in a larger cohort of OMPC is necessary. Clinical trial information: NCT04011410 .