Purpose: Alterations in DNA damage repair (DDR) pathway genes occur in 20-25% of men with metastatic castration-resistant prostate cancer (mCRPC). Although poly (adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi) have been shown to benefit men with mCRPC harboring DDR defects due to mutations in BRCA1/2 and ATM, additional treatments are necessary because the effects are not durable. Experimental Design:We performed transcriptomic analysis of publicly available mCRPC cases, comparing BRCA2-null to BRCA2 wild type. We generated BRCA2-null prostate cancer cells using CRISPR/Cas9 and treated these cells with PARPi and SRC inhibitors. We also assessed the antiproliferative effects of combination treatment in 3D prostate cancer organoids. Results:We observed significant enrichment of the SRC signaling pathway in BRCA2-altered mCRPC. BRCA2-null prostate cancer cell lines had increased SRC phosphorylation and higher

2639 Background: Pembrolizumab, a PD-1 immune checkpoint inhibitor (ICI), has demonstrated significant clinical activity in various cancers. Despite a favorable toxicity profile, discontinuation due to adverse events including immune related adverse events (irAE) has been reported. We conducted a meta-analysis of published clinical trials to evaluate the tolerability of pembrolizumab in cancer patients. Methods: A systematic review was conducted of relevant studies from the databases of PubMed and abstracts presented at American Society of Clinical Oncology (ASCO) from June 2015 until September 2020. Eligible studies included prospective clinical trials that reported a discontinuation rate due to adverse effects. Incidence, relative risk and 95% confidence intervals (CI) were calculated by employing fixed or random effects models. Results: A total of 6,380 patients with a variety of hematologic and solid malignancies from 20 studies of pembrolizumab were included for analysis. The overall rate of pembrolizumab discontinuation due to adverse events was 8.2% (95% CI: 6.4-10.4%). The discontinuation rate of pembrolizumab was not significantly lower than the chemotherapy controls, with RR of 0.84 (95% CI: 0.58-1.12, p = 0.33). However, the discontinuation rate of pembrolizumab was significantly higher compared to placebo control with RR of 2.20 (95% CI: 1.36-3.54, p < 0.001), and significantly lower compared to ipilimumab with RR of 0.58 (95% CI: 0.34-0.99, p = 0.04) respectively. The discontinuation rate varied widely among different tumor types with the lowest rate of 0.8% (95% CI: 0.2-3%) in gastric cancer, and the highest of 13.5% (95% CI: 10.8-16.8%) in head and neck squamous cell carcinoma. Interestingly, the discontinuation rate varied with pembrolizumab dosing, with the fixed dosing of 200mg being 9.2% (95% CI: 6.9-12%) and the weight-based dosing being 6.5% (95% CI: 4.8-8.8%). The weight-based dosing was associated with a significantly lower discontinuation rate compared to controls with RR of 0.62 (95% CI: 0.47-0.81, p < 0.0001), while the fixed dosing had similar discontinuation rate with RR of 1.03 (95% CI: 0.89-1.20, p = 0.67). Conclusions: The tolerability of pembrolizumab may be comparable to chemotherapy in cancer patients and may vary with its dosing. Future studies are warranted to evaluate the impact of different dosing.

<p>Supplementary tables (except Table S3) and figure captions</p>

<div>AbstractPurpose:<p>Alterations in DNA damage repair (DDR) pathway genes occur in 20%–25% of men with metastatic castration-resistant prostate cancer (mCRPC). Although PARP inhibitors (PARPis) have been shown to benefit men with mCRPC harboring DDR defects due to mutations in <i>BRCA1/2</i> and ATM, additional treatments are necessary because the effects are not durable.</p>Experimental Design:<p>We performed transcriptomic analysis of publicly available mCRPC cases, comparing <i>BRCA2</i> null with <i>BRCA2</i> wild-type. We generated <i>BRCA2</i>-null prostate cancer cells using CRISPR/Cas9 and treated these cells with PARPis and SRC inhibitors. We also assessed the antiproliferative effects of combination treatment in 3D prostate cancer organoids.</p>Results:<p>We observed significant enrichment of the SRC signaling pathway in <i>BRCA2</i>-altered mCRPC. <i>BRCA2</i>-null prostate cancer cell lines had increased SRC phosphorylation and higher sensitivity to SRC inhibitors (e.g., dasatinib, bosutinib, and saracatinib) relative to wild-type cells. Combination treatment with PARPis and SRC inhibitors was antiproliferative and had a synergistic effect in <i>BRCA2</i>-null prostate cancer cells, mCRPC organoids, and Trp53/Rb1-null prostate cancer cells. Inhibition of SRC signaling by dasatinib augmented DNA damage in <i>BRCA2</i>-null prostate cancer cells. Moreover, <i>SRC</i> knockdown increased PARPi sensitivity in <i>BRCA2</i>-null prostate cancer cells.</p>Conclusions:<p>This work suggests that SRC activation may be a potential mechanism of PARPi resistance and that treatment with SRC inhibitors may overcome this resistance. Our preclinical study demonstrates that combining PARPis and SRC inhibitors may be a promising therapeutic strategy for patients with <i>BRCA2</i>-null mCRPC.</p></div>

<div>AbstractPurpose:<p>Alterations in DNA damage repair (DDR) pathway genes occur in 20%–25% of men with metastatic castration-resistant prostate cancer (mCRPC). Although PARP inhibitors (PARPis) have been shown to benefit men with mCRPC harboring DDR defects due to mutations in <i>BRCA1/2</i> and ATM, additional treatments are necessary because the effects are not durable.</p>Experimental Design:<p>We performed transcriptomic analysis of publicly available mCRPC cases, comparing <i>BRCA2</i> null with <i>BRCA2</i> wild-type. We generated <i>BRCA2</i>-null prostate cancer cells using CRISPR/Cas9 and treated these cells with PARPis and SRC inhibitors. We also assessed the antiproliferative effects of combination treatment in 3D prostate cancer organoids.</p>Results:<p>We observed significant enrichment of the SRC signaling pathway in <i>BRCA2</i>-altered mCRPC. <i>BRCA2</i>-null prostate cancer cell lines had increased SRC phosphorylation and higher sensitivity to SRC inhibitors (e.g., dasatinib, bosutinib, and saracatinib) relative to wild-type cells. Combination treatment with PARPis and SRC inhibitors was antiproliferative and had a synergistic effect in <i>BRCA2</i>-null prostate cancer cells, mCRPC organoids, and Trp53/Rb1-null prostate cancer cells. Inhibition of SRC signaling by dasatinib augmented DNA damage in <i>BRCA2</i>-null prostate cancer cells. Moreover, <i>SRC</i> knockdown increased PARPi sensitivity in <i>BRCA2</i>-null prostate cancer cells.</p>Conclusions:<p>This work suggests that SRC activation may be a potential mechanism of PARPi resistance and that treatment with SRC inhibitors may overcome this resistance. Our preclinical study demonstrates that combining PARPis and SRC inhibitors may be a promising therapeutic strategy for patients with <i>BRCA2</i>-null mCRPC.</p></div>