Porcu, Raphaelle

Abstract Purpose: Men with metastatic castration-resistant prostate cancer (mCRPC) have limited treatment options after progressing on hormonal therapy and chemotherapy. Here, we evaluate the safety and efficacy of atezolizumab (anti–PD-L1) + radium-223 dichloride (radium-223) in men with mCRPC. Patients and Methods: This phase Ib study evaluated atezolizumab + radium-223 in men with mCRPC and bone and lymph node and/or visceral metastases that progressed after androgen pathway inhibitor treatment. Following safety assessment of concurrent dosing, 45 men were randomized 1:1:1 to concurrent or one of two staggered dosing schedules with either agent introduced one cycle before the other. This was followed by a safety–efficacy expansion cohort (randomized 1:1:1). The primary endpoints were safety and objective response rate (ORR) by RECIST 1.1. Secondary endpoints included radiographic progression-free survival (rPFS), PSA responses, and overall survival (OS). Results: As of October 4, 2019, 44 of 45 men were evaluable. All 44 had ≥1 all-cause adverse event (AE); 23 (52.3%) had a grade 3/4 AE. Fifteen (34.1%) grade 3/4 and 3 (6.8%) grade 5 AEs were related to atezolizumab; none were related to radium-223. Confirmed ORR was 6.8% [95% confidence interval (CI), 1.4–18.7], median rPFS was 3.0 months (95% CI, 2.8–4.6), median PSA progression was 3.0 months (95% CI, 2.8–3.3), and median OS was 16.3 months (95% CI, 10.9–22.3). Conclusions: This phase Ib study demonstrated that atezolizumab + radium-223, regardless of administration schedule, had greater toxicity than either drug alone, with no clear evidence of additional clinical benefit for patients with mCRPC and bone and lymph node and/or visceral metastases.

5565 Background: mCRPC patients (pts) tend to have a poor prognosis and limited treatment (tx) options, especially those with concomitant bone metastases (mets). We explored the ability of combination tx with atezo (anti–PD-L1) and r-223 (α-particle emitter) to stimulate anti-tumor immunity in mCRPC pts. Methods: This Phase Ib study evaluated the safety and tolerability of atezo + r-223 in pts with mCRPC and multiple bone mets, visceral mets and/or lymphadenopathy who progressed after androgen pathway inhibitor tx. The initial cohort phase evaluated the safety and tolerability of a concurrent dosing schedule (CDS), in which atezo and r-223 were administered on the same day. Following assessment of CDS, pts were randomized 1:1:1 to CDS or 1 of 2 staggered dosing schedules (atezo or r-223 introduced a full cycle before the other). This was followed by an expansion of enrollment (randomized 1:1:1). Pts got atezo 840 mg IV q2w and r-223 at 55 kBq/kg IV 6 times at 4-wk intervals until unacceptable toxicity or loss of clinical benefit. Exploratory measures of efficacy included investigator-assessed ORR (RECIST 1.1), PSA response rate, time to PSA progression, radiographic PFS (rPFS; PCWG2 criteria) and OS. Biopsy samples were collected at baseline and prior to cycle 2 to evaluate changes in the tumor microenvironment during tx. Results: As of Oct 4, 2019, 45 pts were enrolled and 44 had evaluable data. Baseline characteristics were generally similar across groups. All 44 evaluable pts had ≥ 1 all-cause AE; 23 (52.3%) had Gr 3-4 AE. Eight pts (18.2%) had Gr 5 AE as per protocol reporting of deaths; 4 (9.1%) were from disease progression. Median follow-up was 13.9 mo (range, 1.7–34.2). Confirmed ORR was 6.8% (95% CI: 1.43, 18.66). Confirmed PSA response rate was 4.5% and median time to PSA progression was 3.0 mo (95% CI: 2.8, 3.3). Median rPFS was 3.0 mo (95% CI: 2.8, 4.6) and median OS was 16.3 mo (95% CI: 10.9, 22.3). Changes in PD-L1 and CD8 IHC were consistent with the known mechanism of action of atezo, as were changes in alkaline phosphatase with radium. Conclusions: No dose-limiting toxicities, safety signals, or changes in serum biomarkers were observed beyond the known safety profiles of atezo and r-223. This Phase 1b study did not seem to show clinical benefit from combination tx. Ongoing subgroup and biomarker analyses may provide additional insights. Studies of PD-1/PD-L1 targeted therapies in combination with tumor-directed radiation in molecularly selected mCRPC pts are planned or underway. Clinical trial information: NCT02814669 .