The Achilles heel of precision AKT-targeted therapies in advanced prostate cancer: therapeutic promise constrained by the test.

Metastatic prostate cancer management: 20 years of progress

Metastatic Burden in Hormone-Naive Prostate Cancer: A Tale of Two Subgroups

With new therapies for metastatic prostate cancer, patients are living longer, increasing the need for better understanding of the impact of comorbid disease. Prescription medications may risk-stratify patients independent of established methods, such as the Charlson Comorbidity Index (CCI) and guide treatment selection. In a nationwide retrospective study of US Veterans, we used multivariable logistic regression and Cox proportional hazard modeling to evaluate the association between number and class of prescription medications and overall survival (OS) with age, race, body-mass index, prostate specific antigen (PSA), and Charlson comorbidities as covariates in veterans treated for de novo metastatic hormone sensitive prostate cancer (mHSPC) between 2010-2021. Among 8,434 Veterans, a median of nine medications and five medication classes were filled in the year prior to initial treatment with abiraterone or enzalutamide for mHSPC. Veterans on 1-4 medications had an average survival of 38 months compared to 5-9 medicines (33 months), 10-14 medicines (27 months), and 15+ medicines (22 months) (p<0.001). After adjusting for age, race, body mass index (BMI), PSA, CCI, and year of diagnosis, both the number of medications and medication classes were associated with increased mortality. The adjusted hazard ratio (aHR) [95% confidence interval (CI)] was 1.03 (1.02-1.03) for the number of medications and 1.05 (1.04-1.07) for medication classes. Medications within ATC B (blood/blood forming organs), ATC C (cardiovascular), and ATC N (nervous) were associated with worse OS, with aHRs of 1.14 (1.07, 1.21), 1.14 (1.06, 1.22), and 1.12 (1.06, 1.19), respectively. The number and class of medications were independently associated with overall survival in patients undergoing treatment for mHSPC. With new therapies for advanced prostate cancer, patients are living longer, highlighting the need for a better understanding of the impact of comorbid diseases. Simple methods to assess disease burden and prognosticate survival have the potential to guide treatment decisions.

Clinical Outcomes of First-line Abiraterone Acetate or Enzalutamide for Metastatic Castration-resistant Prostate Cancer After Androgen Deprivation Therapy+ Docetaxel or ADT Alone for Metastatic Hormone-sensitive Prostate Cancer.

Novel therapies for advanced prostate cancer: have we have widened the goal posts too far?

Targeting Metastatic Hormone Sensitive Prostate Cancer: Chemohormonal Therapy and New Combinatorial Approaches.

TPS214 Background: Multiple systemic therapies have resulted in improved overall survival (OS) for mHSPC, including several AR-targeted agents (ARTA) and docetaxel chemotherapy. However, patients (pts) with high volume de novo metastatic prostate cancer still only have an OS of approximately 50 months. Thus, more effective combination strategies for initial treatment of mHSPC are urgently needed. CABO, a multi-tyrosine kinase inhibitor (including MET, VEGFR-1, -2,-3, AXL) has shown synergy with ABI as well as with CPI in preclinical studies. CABO and ABI have demonstrated an acceptable safety profile in metastatic castration resistant prostate cancer (mCRPC) (Choudhury et al Prostate 2018), and CABO and atezolizumab (ATEZO) in combination have showed a promising efficacy signal and manageable safety profile in mCRPC (COSMIC-021, NCT03170960; Agarwal ESMO 2021). The phase 3 CONTACT-02 trial (NCT04446117) is randomizing mCRPC pts to either CABO and ATEZO or a second generation ARTA. Given the robust preclinical and emerging clinical data for the use of both CABO and CPI therapy in advanced prostate cancer and the need to optimize therapy earlier in the course of disease, in the present trial we intend to evaluate the safety and tolerability of ABI, CABO, and CPI in mHSPC. Methods: CABIOS (NCT04477512) is a phase Ib, single center, open label trial of ABI, CABO and the CPI nivolumab (NIVO), an anti-PD-1 monoclonal antibody, in pts with mHSPC. Key inclusion criteria include histologically or cytologically confirmed metastatic prostate adenocarcinoma without neuroendocrine/small cell differentiation and radiographic evidence of metastatic disease. Ongoing androgen deprivation (ADT) within 12 weeks of study start is allowed. Key exclusion criteria include evidence of castration resistance, prior treatment with second-generation androgen receptor inhibitors, CYP17 inhibitors, CABO, or checkpoint inhibitor immunotherapy (anti-PD-1/PD-L1, CTLA-4), active autoimmune disease, and ongoing treatment with systemic corticosteroids daily. The primary objective of the trial is evaluation of the safety and tolerability of this combination therapy in the trial population; the primary endpoint is the frequency of dose-limiting toxicities (DLTs) as measured by CTCAE v5.0. The study will employ a 3 + 3 design evaluating ABI 1,000 mg once daily with prednisone 5 mg daily, NIVO 480 mg IV every 4 weeks, and a CABO starting dose of 20 mg once daily at dose level 1 (DL1). If 0 of 3 pts at DL1 experience a DLT, 3 pts will be enrolled at DL2 with CABO 40 mg once daily. If 1 of 3 pts at DL1 experience a DLT, 3 additional pts will be enrolled at DL1. If 0 of 3 pts experience a DLT at DL2, the study will move to a recommended phase 2 dose (RP2D) expansion cohort. Total sample size of approximately 20 pts is expected depending on DLT frequencies. Enrollment is ongoing. Clinical trial information: NCT04477512.

Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline PART II.

Prostate cancer is the second most common cancer and the fifth leading cause of cancer death in males worldwide, with over 1.4 million cases and more than 397,000 deaths in 2022. Up to one-third of patients with prostate cancer will develop metastases, which are significantly associated with mortality. Hormone-sensitive prostate cancer that is already metastatic at diagnosis (de novo metastatic hormone-sensitive prostate cancer [mHSPC]) is an aggressive form of the disease that is associated with poor survival outcomes. Loss of function of the tumor suppressor, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), is a key driver in the development of prostate cancer, particularly metastatic disease. Patients with a tumor biomarker of PTEN loss or deficiency have a particularly poor prognosis. This article summarizes a symposium, ‘Pioneering Precision Medicine in Prostate Cancer, The Role of PTEN in Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)’, held at the 2025 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium in San Francisco, California, USA, in February 2025. The article highlights the unmet need in mHSPC, the evolving treatment landscape for this disease, and the poor prognosis linked to PTEN loss or deficiency in de novo mHSPC. The pathways and biomarkers associated with metastatic prostate cancerare explored, with a particular focus on the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/PTEN pathway. The therapeutic rationale for dual targeting of androgen receptor (AR) and AKT pathways, the outcomes of PTEN deficiency in prostate cancer, and PTEN deficiency as a biomarker for prostate cancer, are also discussed. Diagnostic technologies to test for PTEN deficiency and PTEN alterations in metastatic prostate cancer are outlined, and the potential relationship between the extent of PTEN deficiency and the sensitivity of targeted treatment is considered. In addition, topline findings released after the symposium with the AKT inhibitor, capivasertib, in combination with abiraterone and androgen deprivation therapy (ADT) in patients with PTEN-deficient de novo mHSPC in the Phase III study, CAPItello-281, are presented in this article.

Chemotherapy, not androgen receptor-targeted therapy should be used upfront for metastatic hormone-sensitive prostate cancer. PRO: docetaxel chemotherapy should be the default consideration in metastatic hormone-sensitive prostate cancer.

Second-line treatment options in metastatic castration-resistant prostate cancer: A comparison of key trials with recently approved agents

Prostate cancer is one of the most common cancers in men. Despite the development of a variety of therapeutic agents to treat either metastatic hormone-sensitive prostate cancer, advanced prostate cancer, or nonmetastatic/metastatic castration-resistant prostate cancer, the progression or spread of the disease often cannot be avoided. Additionally, the development of resistance of prostate cancer cells to available therapeutic agents is a well-known problem. Despite extensive and cost-intensive research over decades, curative therapy for metastatic prostate cancer is still not available. Therefore, additional therapeutic agents are still needed. The animal kingdom offers a valuable source of natural substances used for the treatment of a variety of diseases. Bee venom of the honeybee is a mixture of many components. It contains proteins acting as enzymes such as phospholipase A2, smaller proteins and peptides such as melittin and apamin, phospholipids, and physiologically active amines such as histamine, dopamine, and noradrenaline. Melittin has been shown to induce apoptosis in different cancer cell lines, including prostate cancer cell lines. It also influences cell proliferation, angiogenesis, and necrosis as well as motility, migration, metastasis, and invasion of tumour cells. Hence, it represents an interesting anticancer agent. In this review article, studies about the effect of bee venom components on prostate cancer cells are discussed. An electronic literature research was performed utilising PubMed in February 2021. All scientific publications, which examine this interesting subject, are discussed. Furthermore, the different types of application of these promising substances are outlined. The studies clearly indicate that bee venom or melittin exhibited anticancer effects in various prostate cancer cell lines and in xenografts. In most of the studies, a combination of bee venom or the modified melittin with another molecule was utilised in order to avoid side effects and, additionally, to target selectively the prostate cancer cells or the surrounding tissue. The studies showed that systemic side effects and unwanted damage to healthy tissue and organs could be minimised when the anticancer drug was not activated until binding to the cancer cells or the surrounding tissue. Different targets were used, such as the matrix metalloproteinase 2, hormone receptors expressed by prostate cancer cells, the extracellular domain of PSMA, and the fibroblast activation protein occurring in the stroma of prostate cancer cells. Another approach used loaded phosphate micelles, which were cleaved by the enzyme secretory phospholipase A2 produced by prostate cancer cells. In a totally different approach, targeted nanoparticles containing the melittin gene were used for prostate cancer gene therapy. By the targeted nonviral gene delivery, the gene encoding melittin was delivered to the prostate cancer cells without systemic side effects. This review of the scientific literature reveals totally different approaches using bee venom, melittin, modified melittin, or protoxin as anticancer agents. The toxic agents acted through several different mechanisms to produce their anti-prostate cancer effects. These mechanisms are not fully understood yet and more experimental studies are necessary to reveal the complete mode of action. Nevertheless, the researchers have conducted pioneering work. Based on these results, further experimental and clinical studies about melittin and modifications of this interesting agent deriving from nature are necessary and could possibly lead to a complementary treatment option for prostate cancer.

This review examines the development and efficacy of novel treatment options for advanced prostate cancer and discusses novel therapies that are on the horizon. Since the introduction of docetaxel as the standard treatment for patients with metastatic castration-resistant prostate cancer (CRPC), a number of different agents have been tested but failed to demonstrate improvement in overall survival (OS). Recently, three novel compounds have demonstrated OS benefit and one other showed reduction in skeletal-related events (SREs). Sipuleucel-T, a novel vaccine, was approved by the US regulatory authorities in April 2010 for patients with early advanced prostate cancer. A new taxane, cabazitaxel, and abiraterone acetate, an androgen biosynthesis inhibitor, have shown an OS benefit in advanced CRPC after docetaxel, leading to drug approval. A new bone-targeting agent, denosumab, a receptor activator of nuclear factor κB ligand (RANKL) antagonist, showed a modest reduction in SREs in comparison to zoledronic acid in patients with bone metastases. Other promising novel agents are currently being tested in the clinical setting of advanced CRPC. These include, androgen receptor inhibitors (MDV3100), androgen biosynthesis inhibitors, angiogenesis inhibitors (thalidomide, lenalidomine, aflibercept, tasquinimod), a novel form of radiotherapy (radium-223), and immune-modulating compounds (PROSTVAC-VF). Improvements in progression-free survival and OS rates, observed with novel agents, in metastatic prostate cancer have led to a shift in treatment paradigm. The challenge will be to position the current established and expected novel treatments in the new landscape of metastatic prostate cancer and to determine at what point and time in the disease course they can best be administered.

To establish a novel quantitative method that automatically excludes the red bone marrow and accurately quantifies the tumor volume on whole-body magnetic resonance imaging using updated imaging software. To also evaluate the association between the quantified tumor volume and the prognosis of patients with metastatic prostate cancer. This prospective analysis included patients diagnosed with metastatic hormone-sensitive or metastatic castration-resistant prostate cancer between 2017 and 2022. We developed an imaging software (Attractive BD_Score) that analyzed whole-body diffusion-weighted and in-phase and opposed-phase T1-weighted images to automatically exclude the red bone marrow. The quantified tumor volume was compared with that quantified by traditional whole-body diffusion-weighted imaging without red bone marrow exclusion. Prostate-specific antigen progression-free survival, time-to-pain progression, and overall survival were evaluated to assess the prognostic value of the quantified tumor volume. The quantified tumor volume was significantly smaller than that quantified by the traditional method in metastatic hormone-sensitive (median: 81.0 ml vs. 149.4ml) and metastatic castration-resistant (median: 29.4 ml vs. 63.5ml) prostate cancer. A highly quantified tumor volume was associated with prostate-specific antigen progression-free survival (p= 0.030), time-to-pain progression (p=0.003), and overall survival (p= 0.005) in patients with metastatic hormone-sensitive prostate cancer and with poor prostate-specific antigen progression-free survival (p= 0.001) and time-to-pain progression (p= 0.005) in patients with metastatic castration-resistant prostate cancer. Our imaging method could accurately quantify the tumor volume in patients with metastatic prostate cancer. The quantified tumor volume can be clinically applied as a new prognostic biomarker for metastatic prostate cancer.

89Zr-MSTP2109A, A Novel Antibody Based Radiotracer to Evaluate and Guide the Clinical Translation of Antibody-Drug Conjugates Targeting STEAP1