In the setting where a prostate MRI identifies a lesion suspicious for cancer (e.g., PI-RADS 3 to 5) among patients who are biopsy-naïve, clinicians will be confronted with a decision to proceed with targeted biopsies along with systematic biopsies, or to proceed with targeted biopsies alone. A number of observational studies have shown a higher detection of clinically significant prostate cancer when both targeted and systematic biopsies are combined.128, 130, 154-159 In a study of 300 patients with either a PSA ≥ 4 ng/mL or an abnormal DRE, fusion biopsy detected 69%, systematic 12-core biopsy detected 80%, and combination of both yielded 87% of all GG2+ tumors.155 These and other studies are further supported by a larger study that included a mix of biopsy-naïve patients and patients with prior biopsies. In this study of over 400 biopsy-naïve patients, a combination of targeted and systematic biopsies resulted in 9.9% greater detection of cancer than either approach alone.160 Further, this study noted that the combination approach resulted in the lowest rate of surgical upgrading (3.5%) in a subset of patients who underwent prostatectomy.160 It has been hypothesized that systematic biopsies may improve detection of GG2+ cancer in some cases by sampling the target when the targeted cores may have missed the target.161, 162 Systematic biopsy alone detected 1.9% high-grade cancers (defined as GG3 or higher) that MRI-targeted biopsy failed to detect. In a post hoc analysis of this study, an expert genitourinary radiologist reviewed all the prostate MRIs and tracked the systematic and MRI targeted biopsy cores from these 41 patients. The registration targeting error during the MRI-ultrasound fusion biopsy accounted for 51% of the misses, with MRI invisible lesions or missed MRI lesions by radiology accounting for the remainder.163 While not widely available, use of an in-bore biopsy approach eliminates the co-registration error but does not allow for systematic biopsy.164 In contrast, Kim et al. found little difference in detection between the combined approach and targeted cores.158 In reviewing the literature, the Panel found published studies have used a variety of fusion platforms, biopsy approaches, and systematic templates, making direct comparison prohibitive. In most cases an indication for a fusion biopsy was PI-RADS 3 to 5 findings on MRI. The tradeoff for finding more GG2+ cancer, with adding a systematic biopsy to the target only approach, is that more GG1 cancer will also be diagnosed. In recent publications, this rate has been reported between 1.2% and 5% GG1.119, 160 Following the literature review window for these guidelines, a randomized trial comparing targeted biopsy alone versus targeted plus systematic biopsies among patients with PI-RADS 3 to 5 findings on MRI was published.119 This study demonstrated a 50% reduction in detection of GG1 cancers (absolute reduction from 1.2% to 0.6%), and a 27% reduction in findings of GG2+ cancers (absolute reduction from 1.1% to 0.8%), in the target-only arm. Although the decreased detection of GG2+ cancer detection was not statistically significant, (the study was not powered to detect this difference) it may well be clinically significant.119 As in the PSA screening setting, use of SDM is highly recommended given the uncertainty involved.