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The APC I1307K germline variant confers an increased risk of several malignancies. Here, we report a higher than expected prevalence of treatment-emergent neuroendocrine transformation among men with prostate cancer and germline APC I1307K when compared to a control cohort. If validated, this finding could represent a new biomarker for this aggressive prostate cancer subtype. Introduction: Somatic mutations in the Wnt signaling gene Adenomatous Polyposis Coli (APC) promote metastatic prostate cancer (PCa) progression. Less is known regarding the impact of germline APC mutations on PCa outcomes. We sought to investigate the prevalence of aggressive variant PCa (AVPC) and treatment-emergent neuroendocrine PCa (t-NEPC) in patients with the germline APC I1307K variant, an alteration found in 7% of Ashkenazi Jewish men. Materials and Methods: We report a retrospective cohort study comparing patients with PCa and either APC I1307K germline mutation, APC somatic mutations, or unselected patients. Proportions of patients with AVPC among all the cases were estimated along with 95% Clopper-Pearson exact confidence intervals (CI). Odds ratios with 95% CI were provided for the prevalence of t-NEPC and AVPC in patients with germline APC I1307K compared to patients with frameshift alterations in APC. Results: From 2016-2022, 18 patients with PCa at 3 institutions with the germline APC (I1307K) mutation were identified. Clinically-defined AVPC was found in 8 of the 15 cases with metastatic disease (53%; 95% CI: 26%-79%). Combined somatic alterations in two or more of RB1, TP53 or PTEN (molecularly-defined AVPC) were found in 5/18 cases (28%; 95% CI: 10%-54%). When compared to 20 patients with APC somatic frameshift mutations, patients with the germline APC I1307K variant had a significantly increased risk of AVPC (OR 7.2; 95% CI 1.27, 40.68). Conclusion: PCa that develops in the presence of the germline APC I1307K mutation appear to be enriched for clinically-defined and molecularly-defined AVPC and in particular, for t-NEPC. [ABSTRACT FROM AUTHOR]

• PARP inhibitors can be efficacious in a selected cohort of prostate cancer patients with HRD. • A significant fraction of PARP inhibitor resistance occurs due to adoption of PARylation bypass mechanisms, while still maintaining HRRd status in the cancer cell. • In this subset of patients, Carboplatin can be considered for salvage if reversion mutations are not detected following PARP inhibitor failure. [ABSTRACT FROM AUTHOR]

Bipolar androgen therapy (BAT) is a novel treatment strategy for patients with metastatic castration-resistant prostate cancer (mCRPC). We retrospectively identified patients with mCRPC that achieved deep PSA responses to BAT. All patients with available next-generation molecular sequencing harbored pathogenic mutations in TP53 and/or a homologous recombination DNA repair gene. Background: Bipolar androgen therapy (BAT) is an emerging treatment strategy for men with metastatic castration resistant prostate cancer (mCRPC) whereby serum testosterone is cycled from supraphysiologic to near-castrate levels each month. BAT has been shown to induce clinical responses in a significant proportion of patients, some of which are extreme. We explored the clinical and molecular characteristics of patients with mCRPC who achieved deep responses to BAT. Methods: We conducted a retrospective analysis of patients with mCRPC treated with BAT at Johns Hopkins. We identified 22 of 114 (19%) patients with mCRPC who achieved =70% PSA reductions upon treatment with BAT. All patients were treated using 400 mg testosterone cypionate intramuscularly every 28 days, together with continuous LHRH agonist therapy. Clinical-grade DNA sequencing was obtained using commercially available assays. Results: Somatic next-generation sequencing was obtained for 15 of 22 (68%) patients. Of these 15 extreme PSA responders with sequencing data available, All 15 of 15 (100%) harbored a pathogenic mutation in TP53 and/or a homologous recombination DNA repair (HRD) gene. Among the subset of patients with measureable disease (N = 15), 10 patients (67%) achieved an objective response including one patient with a complete response. The median radiographic progressionfree survival of these deep PSA responders was 11.3 months (95% CI, 7.9-25.0 months). Conclusions: We observed an enrichment of TP53 and HRD mutations in mCRPC patients with extreme PSA responses to BAT, with durability lasting about a year. These data support the hypothesis that BAT may most benefit patients with DNA repair-deficient mCRPC. Further studies of BAT in biomarker-selected mCRPC populations (ie, TP53/HRD-mutated) are warranted. [ABSTRACT FROM AUTHOR]

Rationale and Objectives: The purpose of this study was to investigate the use of multiparametric, whole-body, diffusion-weighted imaging (WB-DWI) and apparent diffusion coefficient (ADC) maps with T2-weighted magnetic resonance imaging (MRI) at 3T for the detection and monitoring of metastatic disease in patients.Materials and Methods: Fifty-four participants (32 healthy subjects and 22 patients) were scanned with WB-DWI methods using a 3T MRI scanner. Axial, sagittal, or coronal fat-suppressed T2-weighted (T2WI), T1-weighted (T1WI), and DWI images were acquired. Total MRI acquisition and set-up time was approximately 45 minutes. Metastatic disease on MRI was confirmed based on T2WI characteristics. The number of lesions was established on computed tomography (CT) or positron emission tomography (PET-CT). Whole-body ADC maps and T2WI were constructed, and region-of-interests were drawn in normal and abnormal-appearing tissue for quantitative analysis. Statistical analysis was performed using a paired t tests and P < .05 was considered statistically significant.Results: There were 91 metastatic lesions detected from the CT or PET-CT with a missed recurrent lesion in the prostate. Multiparametric WB-MRI had excellent sensitivity (96%) for detection of metastatic lesions compared to CT. ADC map values and the ADC ratio in metastatic bone lesions were significantly increased (P < .05) compared to normal bone. In soft tissue, ADC map values and ratios in metastatic lesions were decreased compared to normal soft tissue.Conclusion: We have demonstrated that multiparametric WB-MRI is feasible for oncologic staging to identify bony and visceral metastasis in breast, prostate, pancreatic, and colorectal cancers. WB-MRI can be tailored to fit the patient, such that an "individualized patient sequence" can be developed for a comprehensive evaluation for staging and response during treatment. [ABSTRACT FROM AUTHOR]

Abstract: Patients with castration-resistant prostate cancer (CRPC) frequently have metastases to the bone, which may cause pain and lead to a deterioration in quality-of-life. Bone-seeking radiopharmaceuticals are agents which, when administered systemically, localize to the site of bone metastases and deliver focal radiation there. In this review, we will summarize the current literature on bone-targeting radiopharmaceuticals for CRPC, focusing on strontium-89, samarium-153, rhenium-186 and radium-223. We will discuss their indications, clinical efficacy, and toxicities and highlight some of the challenges in optimizing treatment with these agents. Historically, clinical trials with these drugs have failed to demonstrate survival improvements, restricting their use for palliative purposes only. Radium-223 is the first agent in this class to show an overall survival advantage in CRPC patients with bone metastases. This landmark finding will likely have a considerable impact on the treatment paradigm of bone-metastatic CRPC, and will pave the way for further developments in the future. [Copyright &y& Elsevier]

Abstract: Virtually all patients that succumb to prostate cancer die of metastatic castration-resistant disease. Although docetaxel is the standard of care for these patients and is associated with a modest prolongation of survival, there is an urgent need for novel treatment strategies for metastatic prostate cancer. In the last several years, great strides have been made in our understanding of the biological and molecular mechanisms driving prostate cancer growth and progression, and this has resulted in widespread clinical testing of numerous new targeted therapies. This review discusses some of the key therapeutic agents that have emerged for the treatment of metastatic castration-resistant prostate cancer in the last 5years, with an emphasis on both molecular targets and clinical trial design. These agents include mammalian target of rapamycin (mTOR) pathway inhibitors, anti-angiogenic drugs, epidermal growth factor receptor (EGFR) inhibitors, insulin-like growth factor (IGF) pathway inhibitors, apoptosis-inducing drugs, endothelin receptor antagonists, receptor activator of nuclear factor κB (RANK) ligand inhibitors, vitamin D analogues, cytochrome P17 enzyme inhibitors, androgen receptor modulators, epigenetic therapies, vaccine therapies, and cytotoxic T lymphocyte-associated antigen (CTLA)-4 blocking agents. [Copyright &y& Elsevier]

Analysis of 27,810 patients with advanced cancers treated with anti-PD-1/L1 therapies shows that immune gene signatures or immune cell infiltration is not universally associated with mutation burden or long-term survivors after immunotherapies across cancer entities. Thus, immunological stratification of tumors has limited bearing on the immunogenicity of tumors or immunotherapy outcomes. [ABSTRACT FROM AUTHOR]

Innovations in imaging and molecular characterisation together with novel treatment options have improved outcomes in advanced prostate cancer. However, we still lack high-level evidence in many areas relevant to making management decisions in daily clinical practise. The 2022 Advanced Prostate Cancer Consensus Conference (APCCC 2022) addressed some questions in these areas to supplement guidelines that mostly are based on level 1 evidence. To present the voting results of the APCCC 2022. The experts voted on controversial questions where high-level evidence is mostly lacking: locally advanced prostate cancer; biochemical recurrence after local treatment; metastatic hormone-sensitive, non-metastatic, and metastatic castration-resistant prostate cancer; oligometastatic prostate cancer; and managing side effects of hormonal therapy. A panel of 105 international prostate cancer experts voted on the consensus questions. The panel voted on 198 pre-defined questions, which were developed by 117 voting and non-voting panel members prior to the conference following a modified Delphi process. A total of 116 questions on metastatic and/or castration-resistant prostate cancer are discussed in this manuscript. In 2022, the voting was done by a web-based survey because of COVID-19 restrictions. The voting reflects the expert opinion of these panellists and did not incorporate a standard literature review or formal meta-analysis. The answer options for the consensus questions received varying degrees of support from panellists, as reflected in this article and the detailed voting results are reported in the supplementary material. We report here on topics in metastatic, hormone-sensitive prostate cancer (mHSPC), non-metastatic, castration-resistant prostate cancer (nmCRPC), metastatic castration-resistant prostate cancer (mCRPC), and oligometastatic and oligoprogressive prostate cancer. These voting results in four specific areas from a panel of experts in advanced prostate cancer can help clinicians and patients navigate controversial areas of management for which high-level evidence is scant or conflicting and can help research funders and policy makers identify information gaps and consider what areas to explore further. However, diagnostic and treatment decisions always have to be individualised based on patient characteristics, including the extent and location of disease, prior treatment(s), co-morbidities, patient preferences, and treatment recommendations and should also incorporate current and emerging clinical evidence and logistic and economic factors. Enrolment in clinical trials is strongly encouraged. Importantly, APCCC 2022 once again identified important gaps where there is non-consensus and that merit evaluation in specifically designed trials. The Advanced Prostate Cancer Consensus Conference (APCCC) provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference aims to share the knowledge of international experts in prostate cancer with healthcare providers worldwide. At each APCCC, an expert panel votes on pre-defined questions that target the most clinically relevant areas of advanced prostate cancer treatment for which there are gaps in knowledge. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients and their relatives as part of shared and multidisciplinary decision-making. This report focuses on the advanced setting, covering metastatic hormone-sensitive prostate cancer and both non-metastatic and metastatic castration-resistant prostate cancer. Report of the results of APCCC 2022 for the following topics: mHSPC, nmCRPC, mCRPC, and oligometastatic prostate cancer. At APCCC 2022, clinically important questions in the management of advanced prostate cancer management were identified and discussed, and experts voted on pre-defined consensus questions. The report of the results for metastatic and/or castration-resistant prostate cancer is summarised here. • At APCCC 2022, controversies in advanced prostate cancer management were discussed. • More than 100 international experts voted on 198 predefined consensus questions. • APCCC addresses questions with lack of, low-level or conflicting evidence. • The areas covered in this manuscript include: Management of mHSPC, nmCRPC and mCRPC. [ABSTRACT FROM AUTHOR]

Cyclical, high-dose testosterone administration, termed bipolar androgen therapy (BAT), can induce clinical responses and restore sensitivity to androgen signalling inhibition in patients with previously treated castration-resistant prostate cancer (PCa) (CRPC). This trial evaluated whether BAT is a safe and effective first-line hormonal therapy for patients with CRPC. In cohort C of this single-centre, open-label, phase II, multi-cohort trial (RE-sensitizing with Supraphysiologic Testosterone to Overcome REsistance study), 29 patients with CRPC received first-line hormonal therapy with 400 mg of testosterone cypionate intramuscularly every 28 days concurrent with a luteinising hormone-releasing hormone agonist/antagonist. The primary end-point of the study was the PSA 50 response rate to BAT treatment. After treatment with BAT, four of 29 patients (14%; 95% confidence interval [CI]: 4–32%) experienced a PSA 50 response. The median radiographic progression-free survival to BAT was 8.5 months (95% CI: 6.9–15.1) for patients with metastatic CRPC. After progression on BAT, 17 of 18 patients (94%; 95% CI: 73–100%) achieved a PSA 50 response and 15 of 18 patients (83%; 95% CI: 59–96) achieved a PSA 90 response on abiraterone or enzalutamide. Twelve of 15 patients (80%; 95% CI: 52–96) with metastatic CRPC remain on abiraterone or enzalutamide with a median duration of follow-up of 11.2 months. As first-line hormonal treatment for CRPC, BAT was well tolerated and resulted in prolonged disease stabilisation. After progression on BAT, patients had favourable responses to second-generation androgen receptor–targeted therapy. ClinicalTrials.gov NCT02090114 Image 1 • Prostate cancer (PCa) adapts to low testosterone by upregulating the androgen receptor (AR). • High AR is a therapeutic vulnerability to bipolar androgen therapy (BAT). • This is a trial of BAT as first-line hormonal therapy for patients with castration-resistant PCa (CRPC). • BAT produced prostate-specific antigen and objective responses in a subset of patients. • BAT appeared to sensitise CRPC to subsequent androgen ablative therapy. [ABSTRACT FROM AUTHOR]

Purpose: Metastasis-directed therapy (MDT) is increasingly used in castration-sensitive oligometastatic prostate cancer because it prolongs progression-free survival (PFS) and androgen deprivation free survival. Here we describe patterns of recurrence and identify modes of progression after MDT using SABR.Methods and Materials: Two hundred fifty-eight patients with castration-sensitive oligometastatic prostate cancer (≤5 lesions at staging) were retrospectively identified from a multi-institutional database. Descriptive patterns of recurrence and modes of progression were reported. Other outcomes including median time to prostate-specific antigen (PSA) recurrence, time to next intervention, distant metastasis-free survival, overall survival, and biochemical PFS (bPFS) were reported. Survival analysis was performed using the Kaplan-Meier method, and multivariable analysis was performed.Results: Median follow-up was 25.2 months, and 50.4% of patients received concurrent androgen deprivation. Median time to PSA recurrence was 15.7 months, time to next intervention was 28.6 months, distant metastasis-free survival was 19.1 months, and bPFS was 16.1 months. Two-year overall survival was 96.8%. On multivariable analysis, factors associated with bPFS included age (hazard ratio [HR], 1.03; P = .04), N1 disease at diagnosis (HR, 2.00; P = .02), M1 disease at diagnosis (HR, 0.44; P = .01), initial PSA at diagnosis (HR, 1.002; P = <.001), use of androgen deprivation therapy (HR, 0.41; P < .001), pre-SABR PSA (HR, 1.02; P = .01), and use of enhanced imaging for staging (HR, 2.81; P = .001). Patterns of progression favored an osseous component at recurrence; in patients initially treated to a bone lesion alone, the vast majority (86.5%) experienced a recurrence that included an osseous site. Patients treated initially to a nodal site alone tended to recur in a node only (64.5%); however, there was also a significant minority with an osseous component of recurrence at progression (32.3%). Modes of progressors were class I (patients with long term control [no recurrence ≥18 months after therapy]) occurring in 40.9%, class II (oligoprogressors [≤3 lesions at recurrence]) occurring in 36% (including 7.9% of patients with PSA recurrence but no metastatic disease), and class III (polyprogressors [>3 lesions]) occurring in 23.1% of patients.Conclusions: After MDT, the majority of patients have long-term control or oligoprogression (class I or II). Recurrence tended to occur in osseous sites. These findings, if validated, have implications for future integration of MDT and clinical trial design. [ABSTRACT FROM AUTHOR]