177Lu-PSMA-617 and Idronoxil in Men with End-Stage Metastatic Castration-Resistant Prostate Cancer (LuPIN): Patient Outcomes and Predictors of Treatment Response in a Phase I/II Trial.

177Lu-PSMA-617 is an effective therapy for metastatic castration-resistant prostate cancer (mCRPC). However, treatment resistance occurs frequently, and combination therapies may improve outcomes. We report the final safety and efficacy results of a phase I/II study combining 177Lu-PSMA-617 with idronoxil (NOX66), a radiosensitizer, and examine potential clinical, blood-based, and imaging biomarkers. Methods: Fifty-six men with progressive mCRPC previously treated with taxane chemotherapy and novel androgen signaling inhibitor (ASI) were enrolled. Patients received up to 6 doses of 177Lu-PSMA-617 (7.5 GBq) on day 1 in combination with a NOX66 suppository on days 1-10 of each 6-wk cycle. Cohort 1 (n = 8) received 400 mg of NOX66, cohort 2 (n = 24) received 800 mg, and cohort 3 (n = 24) received 1,200 mg. 68Ga-PSMA and 18F-FDG PET/CT were performed at study entry, and semiquantitative imaging analysis was undertaken. Blood samples were collected for analysis of blood-based biomarkers, including androgen receptor splice variant 7 expression. The primary outcomes were safety and tolerability; secondary outcomes included efficacy, pain scores, and xerostomia. Regression analyses were performed to explore the prognostic value of baseline clinical, blood-based, and imaging parameters. Results: Fifty-six of the 100 men screened were enrolled (56%), with a screening failure rate of 26% (26/100) for PET imaging criteria. All men had received prior treatment with ASI and docetaxel, and 95% (53/56) had received cabazitaxel. Ninety-six percent (54/56) of patients received at least 2 cycles of combination NOX66 and 177Lu-PSMA-617, and 46% (26/56) completed 6 cycles. Common adverse events were anemia, fatigue, and xerostomia. Anal irritation attributable to NOX66 occurred in 38%. Forty-eight of 56 had a reduction in prostate-specific antigen (PSA) level (86%; 95% CI, 74%-94%); 34 of 56 (61%; 95% CI, 47%-74%) had a PSA reduction of at least 50%. Median PSA progression-free survival was 7.5 mo (95% CI, 5.9-9 mo), and median overall survival was 19.7 mo (95% CI, 9.5-30 mo). A higher PSMA SUVmean correlated with treatment response, whereas a higher PSMA tumor volume and prior treatment with ASI for less than 12 mo were associated with worse overall survival. Conclusion: NOX66 with 177Lu-PSMA-617 is a safe and feasible strategy in men being treated with third-line therapy and beyond for mCRPC. PSMA SUVmean, PSMA-avid tumor volume, and duration of treatment with ASI were independently associated with outcome.

Phase I/II Trial of the Combination of 177Lutetium Prostate specific Membrane Antigen 617 and Idronoxil (NOX66) in Men with End-stage Metastatic Castration-resistant Prostate Cancer (LuPIN).

BACKGROUND: Trials of lutetium prostate specific membrane antigen (PSMA) in men with metastatic castration-resistant prostate cancer (mCRPC) have demonstrated good safety and efficacy, but combination strategies may improve outcomes. Idronoxil is a synthetic flavonoid derivative with radiosensitising properties. OBJECTIVE: To evaluate the safety and activity of 177Lu PSMA 617 (LuPSMA-617) in combination with idronoxil suppositories (NOX66) in patients with end-stage mCRPC. DESIGN, SETTING, AND PARTICIPANTS: Thirty-two men with progressive mCRPC previously treated with taxane-based chemotherapy (91% treated with both docetaxel and cabazitaxel) and abiraterone and/or enzalutamide were enrolled in this phase I dose escalation study with phase II dose expansion. INTERVENTION: Screening with 68Ga PSMA and 18F-fludeoxyglucose positron emission tomography (PET)/computed tomography (CT) was performed. Men received up to six cycles of LuPSMA-617 (7.5 GBq) on day 1, with escalating doses of NOX66 on days 1-10 of a 6-wk cycle. Cohort 1 (n = 8) received 400 mg and cohort 2 (n = 24) 800 mg of NOX66. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Adverse events (AEs), pain inventory scores, prostate-specific antigen (PSA) response, progression-free survival, and overall survival were evaluated. RESULTS AND LIMITATIONS: Fifty-six men were screened and 32 (57%) were enrolled with a screen failure rate of 21% for PET imaging criteria. Dosing was as follows: 97% (31/32) received two or more doses and 47% (15/32) completed six doses. Common AEs included xerostomia, fatigue, and anaemia. Anal irritation attributable to NOX66 occurred in 28%. PSA responses were as follows: 91% (29/32) had any PSA response (median -74%; 95% confidence interval [CI] 76-97) and 62.5% (20/32) had a PSA fall of >50% (95% CI 45-77). The median PSA progression-free survival was 6.1 mo (95% CI 2.8-9.2) and median overall survival was 17.1 mo (95% CI 6.5-27.1). CONCLUSIONS: NOX66 with LuPSMA-617 is a safe and feasible therapeutic strategy in men treated with third-line therapy and beyond for mCRPC. PATIENT SUMMARY: Addition of NOX66 to 177Lu prostate-specific membrane antigen 617 is safe, and further studies are needed to assess its potential to augment the anticancer effects of LuPSMA-617.

Effectiveness of the progestin-only pill for migraine treatment in women: A systematic review and meta-analysis.

Background Migraine is highly prevalent in women (18%). Peak morbidity affects their most productive years, coinciding with peak fertility. Hormonal contraception is often tailored for migraine prevention. Estrogen-containing contraceptives may be contraindicated in women experiencing migraine with aura due to the risk of vascular events. While improvements in migraine with a progestin-only pill (POP), which inhibits ovulation are documented, the strength and quality of evidence has not been formally evaluated. Objectives To determine the effectiveness of progestin-only contraceptives for migraine treatment by systematic review and meta-analysis. Data sources and selection MEDLINE, EMBASE and Cochrane Libraries were searched (1980 to September 2016) for studies on progestin-only treatments for migraine. Studies in English on >4 non-menopausal women aged 18-50 with migraine diagnosed by formal criteria were included. Data extraction and analysis Data were quality-assessed using the GRADE system. A random effects model was used for pooled analyses. Results Pooled analyses of four studies demonstrated that desogestrel 75 mcg/day, POP significantly but modestly reduced the number of migraine attacks and migraine days. Reduced intensity and duration, reduced analgesic and triptan use were observed, along with improved headache-related quality of life. GRADE analysis indicated evidence was low to very low for each outcome measure. Adverse effects resulted in treatment cessation for <10% of participants. Two studies compared desogestrel POP to a combined oral contraceptive, demonstrating similar migraine outcomes for both treatments. Conclusions The desogestrel POP shows promise in improving migraine in women. Current evidence is observational and based on small samples of women using only one oral progestin-only formulation. Further randomized trials on additional progestin-only contraceptives are required to confirm their role in migraine management.