Utility of pembrolizumab for metastatic castrate resistant prostate cancer with MMR deficiency.

Molecular tumor profiling has become an important diagnostic for prostate cancer, allowing for personalized treatment regimens based on somatic and germline genetic information. We report a 67-year-old patient with metastatic castrate-resistant prostate cancer which was intermittently responsive to androgen-deprivation therapy, docetaxel, abiraterone, radium-223, Sipuleucel-T, and radiotherapy who ultimately demonstrated a remarkable and durable response to pembrolizumab. Our case report underlines the significance of early tumor molecular profiling in aggressive or atypical prostate cancer patients and exhibits the potential for a remarkable clinical response with immunotherapy in candidates with the appropriate tumor profiles.

Bi-specific T-cell engagers (BiTEs) in prostate cancer and strategies to enhance development: hope for a BiTE-r future.

Metastatic castrate resistant prostate cancer (mCRPC) continues to have poor survival rates due to limited treatment options. Bi-specific T cell engagers (BiTEs) are a promising class of novel immunotherapies with demonstrated success in haematological malignancies and melanoma. BiTEs developed for tumour associated antigens in prostate cancer have entered clinical testing. These trials have been hampered by high rates of treatment related adverse events, minimal or transient anti-tumour efficacy and generation of high titres of anti-drug antibodies. This paper aims to analyse the challenges faced by the different BiTE therapy constructs and the mCRPC tumour microenvironment that result in therapeutic resistance and identify possible strategies to overcome these issues.

Atypical Presentation of Metastatic Castrate-resistant Prostate Cancer in a Middle Aged African Male with Good Response to Radioligand Therapy.

Prostate cancer typically follows a characteristic pattern of metastatic spread to the pelvic lymph nodes and bone. Atypical patterns of metastasis are rare but have been documented. In African men, this disease tends to follow a more aggressive course, with the possibility of an atypical site of metastatic spread. We present a case of a 58-year- old African male with metastatic castrate-resistant prostate cancer who presented with both typical and atypical patterns of metastatic disease detected by a fluorine 18 prostate-specific membrane antigen positron emission tomography/computed tomography scan. This patient also had a good response to radioligand therapy.

Bench to Bedside Development of [18F]Fluoromethyl-(1,2-2H4)choline ([18F]D4-FCH).

Malignant transformation is characterised by aberrant phospholipid metabolism of cancers, associated with the upregulation of choline kinase alpha (CHKα). Due to the metabolic instability of choline radiotracers and the increasing use of late-imaging protocols, we developed a more stable choline radiotracer, [18F]fluoromethyl-[1,2-2H4]choline ([18F]D4-FCH). [18F]D4-FCH has improved protection against choline oxidase, the key choline catabolic enzyme, via a 1H/2D isotope effect, together with fluorine substitution. Due to the promising mechanistic and safety profiles of [18F]D4-FCH in vitro and preclinically, the radiotracer has transitioned to clinical development. [18F]D4-FCH is a safe positron emission tomography (PET) tracer, with a favourable radiation dosimetry profile for clinical imaging. [18F]D4-FCH PET/CT in lung and prostate cancers has shown highly heterogeneous intratumoral distribution and large lesion variability. Treatment with abiraterone or enzalutamide in metastatic castrate-resistant prostate cancer patients elicited mixed responses on PET at 12-16 weeks despite predominantly stable radiological appearances. The sum of the weighted tumour-to-background ratios (TBRs-wsum) was associated with the duration of survival.

Circulating Tumour DNA Biomarkers Associated with Outcomes in Metastatic Prostate Cancer Treated with Lutetium-177-PSMA-617.

Background: Lutetium-177-prostate-specific membrane antigen- 617 (Lu-PSMA) is an effective therapy for metastatic castration-resistant prostate cancer (mCRPC). However, treatment responses are heterogeneous despite stringent positron emission tomography (PET)-based imaging selection criteria. Molecularly based biomarkers have potential to refine patient selection and optimise outcomes. Objective: To identify circulating tumour DNA (ctDNA) features associated with treatment outcomes for men treated with Lu-PSMA. Design setting and participants: ctDNA from men treated with Lu-PSMA in combination with idronoxil for progressive mCRPC were analysed using an 85-gene customised sequencing assay. ctDNA fractions, molecular profiles, and the presence of alterations in aggressive-variant prostate cancer (AVPC) genes were analysed at baseline, cycle 3 and at disease progression. Intervention: Men received Lu-PSMA with idronoxil every 6 wk for up to six cycles. Outcome measurements and statistical analysis: Baseline and exit PSMA and fluorodeoxyglucose PET/computed tomography (CT) imaging was conducted at baseline and study exit. Single-photon emission CT (SPECT) scans were performed 24 h after Lu-PSMA. Blood samples were collected at baseline,cycle 3 and at disease progression. Cox proportional-hazards models were used to assess associations and derive hazard ratios (HRs) and confidence intervals (CIs) for associations between molecular factors, imaging features, and clinical outcomes. Results and limitations: Sixty samples from 32 men were sequenced (32 at baseline, 24 at cycle 3, four from patients with disease progression); two samples (baseline, on-treatment) from one individual were excluded from analysis owing to poor quality of the baseline sequencing data. Alterations in AVPC genes were associated with shorter prostate-specific antigen (PSA) progression-free survival (PFS) and overall survival (OS) in univariate (HR 3.4, 95% CI 1.5-7.7; p = 0.0036; and HR 3.3, 95% CI 1.4-7.7; p = 0.0063, respectively) and multivariate analyses (HR 4.8, 95% CI 1.8-13; p = 0.0014; and HR 4.1, 95% CI 1.6-11; p = 0.004). Conclusions: ctDNA alterations in AVPC genes were associated with shorter PSA PFS and OS among men treated with Lu-PSMA and intermittent idronoxil. These candidate molecular biomarkers warrant further study to determine whether they have predictive value and potential to guide synergistic combination strategies to enhance outcomes for men treated with Lu-PSMA for mCRPC. Patient summary: Certain DNA/gene changes detected in the blood of men with advanced prostate cancer were associated with shorter benefit from lutetium PSMA, a targeted radioactive therapy. This information may be useful in determining which men may benefit most from this treatment, but additional research is needed.

Real-world outcomes for first line next-generation hormonal agents in metastatic prostate cancer: a systematic review.

Aim: This review aims to summarize published evidence on the real-world (RW) outcomes of abiraterone or enzalutamide in first-line metastatic castration-resistant prostate cancer. Materials & methods: Studies reporting on RW effectiveness, safety, economic and/or health-related quality of life outcomes were identified by systematic literature review (2011-2021, incl. Embase®, MEDLINE®) and presented in a qualitative synthesis. Risk of bias was assessed using ROBINS-I or the Molinier checklist. Results: 88 studies (n = 83,427 patients) were included. Median progression-free (40 studies) and overall survival (38 studies) ranged from 3.7 to 20.9 months and 9.8 to 45 months, respectively. Survival, safety and economic outcomes were similar across individual treatments, while limited health-related quality of life evidence suggested improvements with abiraterone. Risk of bias was moderate to high. Conclusion: RW outcomes in first-line metastatic castration-resistant prostate cancer remain poor despite treatment, highlighting an unmet need for new regimens. This review was supported by AstraZeneca and Merck Sharp & Dohme.

Lutetium-177 PSMA for the treatment of metastatic castrate resistant prostate cancer: a systematic review.

INTRODUCTION: Metastatic castrate resistant prostate cancer (mCPRC) remains an aggressive form of prostate cancer that no longer responds to traditional hormonal treatment alone. Despite the advent of novel anti-androgen medications, many patients continue to progress, and as a result, there is a growing need for additional treatment options. AREAS COVERED: Lutetium-177 (177Lu) - PSMA-617 has become one of the new frontline treatment options for refractory metastatic castrate resistant prostate cancer after the failure of novel anti-androgen therapy and chemotherapy. Lu-177 has been used in real-world prospective trials and is now becoming utilized in newer phase III clinical trials. Here, we present a comprehensive overview of the current literature, covering retrospective studies, prospective studies, and clinical trials that established Lutetium-177-PSMA-617 (177Lu-PSMA-617) for the treatment of mCRPC. EXPERT OPINION: 177Lu - PSMA-617 has been approved for treatment of mCRPC based on positive phase III studies. While this treatment is tolerable and effective, biomarkers are necessary to determine which patients will benefit. In the future, radioligand treatments will likely be utilized in earlier lines of therapy and potentially in combination with other prostate cancer treatments.

Implications of metastatic stage at presentation in docetaxel naïve metastatic castrate resistant prostate cancer.

BACKGROUND: We performed a secondary analysis of ACIS study to determine if synchronous versus metachronous metastatic presentation has any association with survival and treatment response to dual androgen receptor axis-targeted therapy (ARAT) in docetaxel naïve metastatic castrate resistant prostate cancer (mCRPC). METHODOLOGY: In this phase III randomized controlled trial, docetaxel naïve mCRPC patients were randomized to either apalutamide or placebo combined with abiraterone and prednisone. Multivariable Cox regression models were applied to determine the adjusted association of M-stage with radiographic progression-free survival (rPFS) and overall survival (OS). To determine the heterogeneity of treatment effect based on metastatic stage (M-stage) at presentation, Cox regression was applied with interaction terms between M-stage and treatment. RESULTS: Among 972 patients, 432 had M0, 334 had M1, while M-stage at presentation was unknown in 206. There was no association of M-stage at presentation with rPFS in patients with prior local therapy (LT) (hazard ratio for M1-stage: 1.22 [95% confidence interval: 0.82-1.82]; unknown: 1.03 [0.77-1.38]) or without prior LT (M1-stage: 0.87 [0.64-1.19]; unknown: 1.15 [0.77-1.72]) with no significant heterogeneity. Similarly, there was no association of M-stage with OS in patients with prior LT (M1-stage: 1.04 [0.81-1.33]; unknown: 0.98 [0.79-1.21]) or without prior LT (M1-stage: 0.95 [0.70-1.29]; unknown: 1.17 [0.80-1.71]) with no significant heterogeneity. Based on M-stage at presentation, we did not find any significant heterogeneity in treatment effect on rPFS (interaction p = 0.13), and OS (interaction p = 0.87). CONCLUSION: M-stage at presentation had no association with survival in chemotherapy-naïve mCRPC. We did not find any statistically significant heterogeneity in efficacy of dual ARAT based on synchronous versus metachronous presentation.

Effect of Prior Local Therapy on Response to First-line Androgen Receptor Axis Targeted Therapy in Metastatic Castrate-resistant Prostate Cancer: A Secondary Analysis of the COU-AA-302 Trial.

BACKGROUND: Men with localized prostate cancer are often treated with local therapy (LT). However, a proportion of these patients will eventually develop recurrence and progression requiring systemic therapy. Whether primary LT affects the response to this subsequent systemic treatment is unclear. OBJECTIVE: We investigated whether the receipt of prior prostate-directed LT influenced the response to first-line systemic therapy and survival in docetaxel-naïve metastatic castrate-resistant prostate cancer (mCRPC) patients. DESIGN, SETTING, AND PARTICIPANTS: This is an exploratory analysis of the COU-AA-302 trial, a multicentric double-blinded phase 3 randomized controlled trial in which mCRPC patients with no to mild symptoms were randomized to receive abiraterone plus prednisone or placebo plus prednisone. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We compared the time-varying effects of first-line abiraterone in patients with and without prior LT using a Cox proportional hazard model. The cut points were chosen using grid search, and were 6 and 36 mo for radiographic progression-free survival (rPFS) and overall survival (OS), respectively. We also investigated whether there was any difference in treatment effect on score change (relative to baseline) in various patient-reported outcomes (measured by Functional Assessment of Cancer Therapy-Prostate [FACT-P]) over time depending on the receipt of prior LT. The adjusted association of prior LT with survival was determined using weighted Cox regression models. RESULTS AND LIMITATIONS: Among 1053 eligible patients, 64% (n = 669) received prior LT. We did not find any statistically significant heterogeneity of time-dependent treatment effect from abiraterone on rPFS in patients with (hazard ratio [HR]: 0.36 [95% confidence interval: 0.27-0.49] at ≤6 mo; 0.64 [0.49-0.83] at >6 mo) or without (HR: 0.37 [0.26-0.55] at ≤6 mo; 0.72 [0.50-1.03] at >6 mo) prior LT. Similarly, there was no significant heterogeneity in time-dependent treatment effect on OS with (HR: 0.88 [0.71-1.10] at ≤36 mo; 0.76 [0.52-1.11] at >36 mo) or without (0.78 [0.60-1.01] at ≤36 mo; 0.55 [0.30-0.99] at >36 mo) prior LT. We did not find sufficient evidence of a difference in treatment effect from abiraterone on score change over time in prostate cancer subscale (interaction p = 0.4), trial outcome index (interaction p = 0.8), and FACT-P total score (interaction p = 0.6) depending on the receipt of prior LT. Receipt of prior LT was associated with a significant improvement in OS (average HR: 0.72 [0.59-0.89]). CONCLUSIONS: This study demonstrates that the efficacy of first-line abiraterone and prednisone in docetaxel-naïve mCRPC do not vary significantly based on the receipt of prior prostate-directed LT. Further studies are needed to explore the plausible mechanisms of the association of prior LT with superior OS. PATIENT SUMMARY: This secondary analysis of the COU-AA-302 trial suggests that survival benefits and temporal changes in quality of life with first-line abiraterone in docetaxel-naïve mCRPC do not differ significantly among patients who received versus those who did not receive prior prostate-directed local therapy.

Prognostic Impact of Nutritional Status on Overall Survival and Health-Related Quality of Life in Men with Advanced Prostate Cancer.

PURPOSE: Prognostic role of nutritional status (NS) in patients with metastatic castrate-resistant prostate cancer (mCRPC) is unknown. We hypothesized that patients' NS at the presentation of mCRPC is prognostic for health-related quality of life (HRQoL) and overall survival (OS). METHODS: We conducted a prospective observational study in mCRPC patients. At enrollment, we allocated each patient into one of four NS categories: (i) well-nourished (WN), (ii) nutritional risk without sarcopenia/cachexia (NR), (iii) sarcopenia, or (iv) cachexia. We sought the prognostic role of the NS for OS and HRQoL by regression models. RESULTS: 141 patients were included into our study. When compared to WN patients, those with NR and cachexia had a higher chance of worse HRQoL (OR 3.45; 95% CI [1.28 to 9.09], and OR 4.17; 95% CI [1.28 to 12.5], respectively), as well as shorter OS (HR 2.04; 95% CI [1.19 to 3.39] and HR 2.9; 95% CI [1.56 to 5.41], respectively). However, when accounting for possible confounding factors, we could not prove the significant importance of NS for chosen outcomes. CONCLUSIONS: Suboptimal NS might be an unfavorable prognostic factor for HRQoL and OS. Further interventional studies focusing on therapy or prevention are warranted.

Black Patients with Metastatic Castrate-Resistant Prostate Cancer Have a Shorter Time Interval Between PSA and Clinical Progression on Novel Hormonal Therapies plus Avelumab.

BACKGROUND: Black men are at higher risk for prostate cancer death. Previous studies showed a benefit of different therapies, including immune-based therapy, for Black men with metastatic prostate cancer. We sought to explore the efficacy of the PD-L1 inhibitor avelumab in Black men with metastatic castrate-resistant prostate cancer (mCRPC) progressing after abiraterone or enzalutamide. METHODS: This pilot phase II study enrolled self-identified Black patients who developed mCRPC on next-generation hormonal therapies (NHTs) abiraterone acetate or enzalutamide (NCT03770455). Enrolled patients received avelumab 10mg/kg IV every 2 weeks while remaining on the same NHTs. The primary endpoint of our study was ≥ 50% reduction in prostate specific antigen (PSA) at ≥8 weeks. RESULTS: A total of eight patients were enrolled. The median duration on NHTs prior to enrollment was 364 days (95% CI, 260.9-467.1). The median time to initiate avelumab was 8 days (3-14). With a median follow-up of 196 days, no patients achieved the primary endpoint. The median time to PSA progression was 35 days (95 CI%, 0-94.8) and the median time to radiographic and/or clinical progression was 44 days (95 CI%, 0-118.5). The study was closed prematurely due to safety concerns related to the rapid clinical progression observed in the patients enrolled on study. CONCLUSION: In conclusion, the addition of avelumab to NHT did not demonstrate clinical activity in Black men with new mCRPC. The unexpected short interval between PSA and radiographic and/or clinical progression observed in this study has potential clinical implications.ClinicalTrials.gov Identifier: NCT03770455 (IND number 139559).

The Value of Phenotypic Precision Medicine in Prostate Cancer.

Prostate cancer is the most common cancer among men and the second leading cause of cancer-related death. For patients who develop metastatic disease, tissue-based and circulating-tumor-based molecular and genomic biomarkers have emerged as a means of improving outcomes through the application of precision medicine. However, the benefit is limited to a minority of patients. An additional approach to further characterize the biology of advanced prostate cancer is through the use of phenotypic precision medicine, or the identification and targeting of phenotypic features of an individual patient's cancer. In this review article, we will discuss the background, potential clinical benefits, and limitations of genomic and phenotypic precision medicine in prostate cancer. We will also highlight how the emergence of image-based phenotypic medicine may lead to greater characterization of advanced prostate cancer disease burden and more individualized treatment approaches in patients.

Preclinical Study of Therapeutic Efficacy of a New Russian Radiopharmaceutical 177Lu-DOTA-PSMA.

The therapeutic efficacy of a Russian radiopharmaceutical 177Lu-DOTA-PSMA was studied in vivo using male BALB/c nu/nu (nude) mice with prostate carcinoma 22Rv1 xenografts by tumor growth inhibition criterion. The mean tumor volumes in mice treated with 177Lu-DOTA-PSMA were significantly lower than in animals of the control group. There were no significant differences in the values of tumor growth inhibition between the groups of animals receiving 3.7 or 7.4 MBq of 177Lu-DOTA-PSMA.

Role of Rucaparib in the Treatment of Prostate Cancer: Clinical Perspectives and Considerations.

Prostate cancer is one of the most common types of cancer worldwide and has strong genetic associations. This is important for the development of therapeutics for the condition, as metastatic castrate-resistant prostate cancer (mCRPC) is resistant to standard androgen deprivation therapy (ADT) and has a relatively poor prognosis. We conducted a literature review on rucaparib, a poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor that is currently indicated for the treatment of patients with mCRPC who harbor mutations in BRCA1/2 (homologous recombination repair [HRR] genes) and who have already tried androgen receptor-axis-targeted therapies (ARAT) and a taxane chemotherapy. We describe rucaparib's FDA approval, which was based on the results of the single-arm, open-label, Phase II TRITON2 clinical trial, which found an objective response rate (ORR) of 43.5%, a duration of response (DOR) of over six months in length and an acceptable safety profile. Rucaparib's dosage and clinical considerations for use were also discussed. We also compared rucaparib's use and safety profile with Olaparib, niraparib and talazoparib, three other PARP inhibitors tested for the treatment of mCRPC. Overall, initial results show that the safety profile of all four drugs in mCRPC was relatively similar, and further testing is currently indicated for all four. Differences in their metabolism, however, also warrant further research. The clinical validity of rucaparib will be tested by the follow-up TRITON3 clinical trial, which is comparing the effect of rucaparib compared to standard therapies for mCRPC harboring BRCA1/2 or ATM mutations. Other than TRITON3, other clinical trials are testing rucaparib's ability against other cancers (prostate or otherwise) with HRR mutations, and also the efficacy of combination therapies involving rucaparib. Finally, more research is needed to elucidate rucaparib's effect on HRR mutations other than BRCA1/2. Advancements in understanding the genetic landscape of mCRPC will also assist in understanding rucaparib's full therapeutic potential.

PARP Inhibitors in Advanced Prostate Cancer in Tumors with DNA Damage Signatures.

Since 2010, significant progress has been made in the treatment of metastatic castrate resistant prostate cancer (mCRPC). While these advancements have improved survival, mCRPC remains a lethal disease, with a precision medicine framework that is lagging behind compared to other cancers. Poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) studies in prostate cancer (PCa) have focused primarily on the homologous recombination repair (HRR) genes, specifically BRCA1 and BRCA2. While homologous recombination deficiency (HRD) can be prompted by germline or somatic BRCA1/2 genetic mutations, it can also exist in tumors with intact BRCA1/BRCA2 genes. While the sensitivity of PARPi in tumors with non-BRCA DNA damage signatures is not as well established, it has been suggested that genomic alterations in DNA damage repair (DDR) genes other than BRCA may confer synthetic lethality with PARPI in mCRPC. The aim of this review is to summarize the literature on PARPi and their activity treating BRCA and non BRCA tumors with DNA damage signatures.

Prostate cancer induced bone pain: pathobiology, current treatments and pain responses from recent clinical trials.

PURPOSE: Metastatic spread of prostate cancer to the skeleton may result in debilitating bone pain. In this review, we address mechanisms underpinning the pathobiology of metastatic prostate cancer induced bone pain (PCIBP) that include sensitization and sprouting of primary afferent sensory nerve fibres in bone. We also review current treatments and pain responses evoked by various treatment modalities in clinical trials in this patient population. METHODS: We reviewed the literature using PubMed to identify research on the pathobiology of PCIBP. Additionally, we reviewed clinical trials of various treatment modalities in patients with PCIBP with pain response outcomes published in the past 7 years. RESULTS: Recent clinical trials show that radionuclides, given either alone or in combination with chemotherapy, evoked favourable pain responses in many patients and a single fraction of local external beam radiation therapy was as effective as multiple fractions. However, treatment with chemotherapy, small molecule inhibitors and/or immunotherapy agents, produced variable pain responses but pain response was the primary endpoint in only one of these trials. Additionally, there were no published trials of potentially novel analgesic agents in patients with PCIBP. CONCLUSION: There is a knowledge gap for clinical trials of chemotherapy, small molecule inhibitors and/or immunotherapy in patients with PCIBP where pain response is the primary endpoint. Also, there are no novel analgesic agents on the horizon for the relief of PCIBP and this is an area of large unmet medical need that warrants concerted research attention.

Peripheral gene signatures reveal distinct cancer patient immunotypes with therapeutic implications for autologous DC-based vaccines.

Dendritic cells (DCs) have received considerable attention as potential targets for the development of novel cancer immunotherapies. However, the clinical efficacy of DC-based vaccines remains suboptimal, largely reflecting local and systemic immunosuppression at baseline. An autologous DC-based vaccine (DCVAC) has recently been shown to improve progression-free survival and overall survival in randomized clinical trials enrolling patients with lung cancer (SLU01, NCT02470468) or ovarian carcinoma (SOV01, NCT02107937), but not metastatic castration-resistant prostate cancer (SP005, NCT02111577), despite a good safety profile across all cohorts. We performed biomolecular and cytofluorometric analyses on peripheral blood samples collected prior to immunotherapy from 1000 patients enrolled in these trials, with the objective of identifying immunological biomarkers that may improve the clinical management of DCVAC-treated patients. Gene signatures reflecting adaptive immunity and T cell activation were associated with favorable disease outcomes and responses to DCVAC in patients with prostate and lung cancer, but not ovarian carcinoma. By contrast, the clinical benefits of DCVAC were more pronounced among patients with ovarian carcinoma exhibiting reduced expression of T cell-associated genes, especially those linked to TH2-like signature and immunosuppressive regulatory T (TREG) cells. Clinical responses to DCVAC were accompanied by signs of antitumor immunity in the peripheral blood. Our findings suggest that circulating signatures of antitumor immunity may provide a useful tool for monitoring the potency of autologous DC-based immunotherapy.

Phase II Trial of Sipuleucel-T and Stereotactic Ablative Body Radiation for Patients with Metastatic Castrate-Resistant Prostate Cancer.

(1) We hypothesized that adding concurrent stereotactic ablative radiotherapy (SAbR) would increase the time to progression in patients with metastatic castrate-resistant prostate cancer (mCRPCA) treated with sipuleucel-T. (2) Patients with a history of prostate cancer (PC), radiographic evidence of metastatic disease, and rising prostate-specific antigen (PSA) > 0.2 ng/dL on castrate testosterone levels were enrolled in this single-arm phase II clinical trial and treated with sipuleucel-T and SAbR. The primary endpoint was time to progression (TTP). Cellular and humoral responses were measured using ELISpot and Luminex multiplex assays, respectively. (3) Twenty patients with mCRPC were enrolled and treated with SAbR to 1−3 sites. Treatment was well tolerated with 51, 8, and 4 treatment-related grade 1, 2, and 3 toxicities, respectively, and no grade 4 or 5 adverse events. At a median follow-up of 15.5 months, the median TTP was 11.2 weeks (95% CI; 6.8−14.0 weeks). Median OS was 76.8 weeks (95% CI; 41.6−130.8 weeks). This regimen induced both humoral and cellular immune responses. Baseline M-MDSC levels were elevated in mCRPC patients compared to healthy donors (p = 0.004) and a decline in M-MDSC was associated with biochemical response (p = 0.044). Responders had lower baseline uric acid levels (p = 0.05). No clear correlation with radiographic response was observed. (4) While the regimen was safe, the PC-antigen-specific immune response induced by SAbR did not yield a synergistic clinical benefit for patients treated with sipuleucel-T compared to the historically reported outcomes.

Chimeric Antigen Receptor T-Cell Therapy in Metastatic Castrate-Resistant Prostate Cancer.

Prostate cancer is the most commonly diagnosed solid-organ cancer amongst males worldwide. Metastatic castrate-resistant prostate cancer (mCRPC) is a rapidly fatal end-sequelae of prostate cancer. Therapeutic options for men with mCRPC are limited and are not curative in nature. The recent development of chimeric antigen receptor T-cell (CAR-T) therapy has revolutionised the treatment of treatment-resistant haematological malignancies, and several studies are underway investigating the utility of this technology in the treatment of solid tumours. In this review, we evaluate the current treatment options for men with mCRPC as well as the current landscape of preclinical and clinical trials of CAR-T cell therapy against prostate cancer. We also appraise the various prostate cancer-specific tumour-associated antigens that may be targeted by CAR-T cell technology. Finally, we examine the potential translational barriers of CAR-T cell therapy in solid tumours. Despite preclinical success, preliminary clinical trials in men with prostate cancer have had limited efficacy. Therefore, further clinically translatable preclinical models are required to enhance the understanding of the role of this investigational therapeutic in men with mCRPC. In the era of precision medicine, tailored immunotherapy administered to men in a tumour-agnostic approach provides hope to a group of men who otherwise have few treatment options available.

A Rare Case of Castrate-Resistant Prostate Adenocarcinoma with a Unilateral Testicular Metastasis Mimicking a Primary Testicular Tumour.

Prostate adenocarcinoma with testicular metastasis is rare, present in up to 4% of autopsy diagnoses, and presents symptomatically in less than 0.5% of cases. We report an unusual case of a 55-year-old male who developed a symptomatic testicular metastasis from primary prostate cancer 4 years after initial diagnosis of metastatic castrate-sensitive prostate cancer with nodal and bone-only involvement. The patient had orchidectomy, histologically confirming the metastasis and revealing sparing of the spermatic cord. Prior treatment for his metastatic castrate-sensitive prostate cancer had included androgen deprivation therapy and upfront docetaxel chemotherapy. He had received palliative radiotherapy for symptomatic bone metastasis and managed on enzalutamide for castrate-resistant disease for the preceding 22 months with ongoing PSA response at the time of diagnosis of new testicular metastasis, with a further significant PSA response following his "testicular metastasectomy." At the time of diagnosis of testicular metastasis, he did not have any evidence of other visceral metastases, and his metastatic disease otherwise remained radiologically stable. We describe his disease course, treatment and outline the rare nature of his case of testicular metastasis from prostate cancer.