Avelumab plus SABR encouraging - phase 2 results for mCRPC

[Graham49]

Avelumab combined with stereotactic ablative body radiotherapy in metastatic castration-resistant prostate cancer: the phase 2 ICE-PAC clinical trial

Edmond M Kwan, Lavinia Spain, Angelyn Anton, Chun L Gan, Linda Garrett, Deborah Chang, Elizabeth Liow, Caitlin Bennett, Tiantian Zheng, Jianjun Yu, Chao Dai, Pan Du, Shidong Jia, Heidi Fettke, Claire Abou-Seif, Gargi Kothari, Mark Shaw, Phillip Parente, Carmel Pezaro, Ben Tran, Shankar Siva, Arun A Azad

European Urology 81 (3), 253-262, 2022

Background

Immune checkpoint inhibitor monotherapy in metastatic castration-resistant prostate cancer (mCRPC) has produced modest results. High-dose radiotherapy may be synergistic with checkpoint inhibitors.

Objective

To evaluate the efficacy and safety of the PD-L1 inhibitor avelumab with stereotactic ablative body radiotherapy (SABR) in mCRPC.

Design, setting, and participants

From November 2017 to July 2019, this prospective phase 2 study enrolled 31 men with progressive mCRPC after at least one prior androgen receptor–directed therapy. Median follow-up was 18.0 mo.

Intervention

Avelumab 10 mg/kg intravenously every 2 wk for 24 wk (12 cycles). A single fraction of SABR (20 Gy) was administered to one or two disease sites within 5 d before the first and second avelumab treatments.

Outcomes measurements and statistical analysis

The primary endpoint was the disease control rate (DCR), defined as a confirmed complete or partial response of any duration, or stable disease/non–complete response/non–progressive disease for ≥6 mo (Prostate Cancer Clinical Trials Working Group 3–modified Response Evaluation Criteria in Solid Tumours version 1.1). Secondary endpoints were the objective response rate (ORR), radiographic progression-free survival (rPFS), overall survival (OS), and safety. DCR and ORR were calculated using the Clopper-Pearson exact binomial method.

Results and limitations

Thirty-one evaluable men were enrlled (median age 71 yr, 71% with ≥2 prior mCRPC therapy lines, 81% with >5 total metastases). The DCR was 48% (15/31; 95% confidence interval [CI] 30–67%) and ORR was 31% (five of 16; 95% CI 11–59%). The ORR in nonirradiated lesions was 33% (four of 12; 95% CI 10–65%). Median rPFS was 8.4 mo (95% CI 4.5–not reached [NR]) and median OS was 14.1 mo (95% CI 8.9–NR). Grade 3–4 treatment-related adverse events occurred in six patients (16%), with three (10%) requiring high-dose corticosteroid therapy. Plasma androgen receptor alterations were associated with lower DCR (22% vs 71%, p = 0.13; Fisher’s exact test). Limitations include the small sample size and the absence of a control arm.

Conclusions

Avelumab with SABR demonstrated encouraging activity and acceptable toxicity in treatment-refractory mCRPC. This combination warrants further investigation.

Patient summary

In this study of men with advanced and heavily pretreated prostate cancer, combining stereotactic radiotherapy with avelumab immunotherapy was safe and resulted in nearly half of patients experiencing cancer control for 6 months or longer. Stereotactic radiotherapy may potentially improve the effectiveness of immunotherapy in prostate cancer.

[MateoBeach]

The Good: Some small measure of objective evidence that SABR may provide abscopal enhancement of PDL-1 checkpoint inhibitor. Something to build upon.The Bad: Only half responded at all, and that for just 6 months for rPFS. Worse: So sorry that half were dead at 14 months.

The Ugly: Their primary endpoints seem uninterpretable numerical surrogates. DCR and ORR, what do those even mean?