T-cell Engagers in Prostate Cancer.

Owing to the "cold" tumor immune microenvironment of prostate cancer, immune-targeting agents have shown limited efficacy in patients with advanced prostate cancer, highlighting the need for new therapies with novel mechanisms of action. In this context, T-cell engagers (TCEs), which induce T-cell-mediated killing of cancer cells by binding the CD3 receptor on T cells and a specific tumor antigen expressed on malignant cells, represent a promising therapeutic option. Multiple studies have explored the use of TCEs in previously treated patients with metastatic castration-resistant prostate cancer, and several ongoing trials are currently assessing novel TCEs either as single agents or in combinatorial regimens with molecules with a distinct mechanism of action (eg, androgen receptor pathway inhibitors and other immune-targeting agents).

Therapy-Related Myeloid Neoplasms After [Lu]Lu-PSMA Therapy in Patients with Metastatic Castration-Resistant Prostate Cancer: A Case Series.

[Lu]Lu-prostate-specific membrane antigen (PSMA) therapy has a favorable toxicity profile in patients with metastatic castration-resistant prostate cancer (mCRPC). Therapy-related myeloid neoplasm (t-MN) has been described after [Lu]Lu-DOTATATE but has not, to our knowledge, yet been reported after [Lu]Lu-PSMA. This case series describes 5 patients with mCRPC who developed t-MN after [Lu]Lu-PSMA at our institution.

PSMA-Guided Metastasis-Directed Therapy for Oligometastatic Renal Cell Carcinoma: The Proof-of-Concept PEDESTAL Study.

Metastasis-directed therapy (MDT) in oligometastatic renal cell carcinoma (RCC) is typically based on conventional imaging. Prostate-specific membrane antigen (PSMA) PET/CT has shown superiority over conventional imaging. Our objective was to perform a proof-of-concept study to evaluate the efficacy of PSMA-guided MDT in oligometastatic RCC.

Clinical Trial Protocol for LuCAB: A Phase I-II Trial Evaluating Cabazitaxel in Combination with [Lu]Lu-PSMA-617 in Patients with Metastatic Castration-Resistant Prostate Cancer.

[Lu]Lu-prostate-specific membrane antigen (PSMA)-617 is a standard treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel and an androgen receptor pathway inhibitor. However, for many, responses are short and progression is inevitable. Contributing factors to treatment resistance include molecular heterogeneity with variable PSMA expression, micrometastases that may not absorb sufficient radiation from Lu to result in cell death, and inherent or acquired radioresistance because of genomic alterations or the tumor microenvironment.

Combination Therapies in Locally Advanced and Metastatic Hormone-sensitive Prostate Cancer.

Background And Objective: The treatment landscape for advanced prostate cancer has evolved significantly over the past decade. The introduction of docetaxel, androgen receptor pathway inhibitors (ARPIs), poly(ADP-ribose) polymerase inhibitors, and targeted radionuclides has redefined the treatment paradigm, with a focus now on early treatment intensification through combination therapies. This narrative collaborative review summarises the current evidence of combination therapies in locally advanced and metastatic hormone-sensitive prostate cancer (mHSPC).

BRCA Mutation Testing in Men with Metastatic Castration-Resistant Prostate Cancer: Practical Guidance for Australian Clinical Practice.

Some patients with metastatic castration-resistant prostate cancer (mCRPC) possess germline or acquired defects in the DNA damage repair (DDR) genes BRCA1 and BRCA2. Tumors with BRCA mutations exhibit sensitivity to poly-ADP ribose polymerase inhibitors (PARPi) such as olaparib and rucaparib. As a result, molecular diagnostic testing to identify patients with BRCA mutations eligible for the PARPi therapy has become an integral component of managing patients with mCRPC.

Talazoparib plus enzalutamide in metastatic castration-resistant prostate cancer: Safety analyses from the randomized, placebo-controlled, phase III TALAPRO-2 study.

Background: This detailed analysis further characterizes the safety profile of talazoparib plus enzalutamide in the ongoing randomized, phase III TALAPRO-2 study in patients with metastatic castration-resistant prostate cancer (mCRPC). In both the all-comers and homologous recombination repair (HRR)-deficient populations, talazoparib plus enzalutamide significantly improved radiographic progression-free survival compared with placebo plus enzalutamide.

Methods: The talazoparib plus enzalutamide safety populations in TALAPRO-2 included 398 patients from cohort 1 (all-comers, unselected for HRR gene alterations) and 198 patients from the combined HRR-deficient population (patients from the all-comers population with HRR gene alterations plus subsequently enrolled patients with HRR gene alterations; cohort 2).

Enzalutamide in metastatic hormone-sensitive prostate cancer: A plain language summary of the ARCHES and ENZAMET follow-up studies.

What Is This Summary About?: This summary includes information from the ARCHES and ENZAMET . Both studies looked at enzalutamide treatment for people with metastatic hormone-sensitive prostate cancer (known as mHSPC). In ARCHES, researchers compared the medications enzalutamide + androgen deprivation therapy (known as ADT) with  + ADT.

HSD3B1 genotype and outcomes in metastatic hormone-sensitive prostate cancer with androgen deprivation therapy and enzalutamide: ARCHES.

HSD3B1 encodes 3β-hydroxysteroid dehydrogenase-1, which converts adrenal dehydroepiandrosterone to 5α-dihydrotestosterone and is inherited in adrenal-permissive (AP) or adrenal-restrictive forms. The AP allele is linked to castration resistance, mainly in low-volume tumors. Here, we investigate the association of HSD3B1 alleles with outcomes in ARCHES, a multinational, double-blind, randomized, placebo-controlled phase 3 trial that demonstrated clinical benefit with enzalutamide plus androgen deprivation therapy (ADT) in men with metastatic hormone-sensitive prostate cancer (mHSPC) compared to those treated with placebo plus ADT.

Combination of PARP Inhibitors and Androgen Receptor Pathway Inhibitors in Metastatic Castration-Resistant Prostate Cancer.

Despite recent advances in the treatment of metastatic prostate cancer, progression to a castration-resistant state remains inevitable for most and prognosis is limited. Genetic testing for homologous recombination repair pathway alterations is recommended for all patients with advanced prostate cancer given that a mutation is present in up to 25% of cases. Poly(ADP-ribose) polymerase (PARPis) are now approved for use in patients with metastatic castration-resistant prostate cancer who have progressed on an androgen receptor pathway inhibitor (ARPI) and harbour a germline or somatic homologous recombination repair mutation.

Plain language summary of the results from the TALAPRO-2 study: Talazoparib plus enzalutamide versus placebo plus enzalutamide for patients with advanced prostate cancer.

What Is This Summary About?: This summary describes the results from the TALAPRO-2 research study (also known as a clinical trial). The TALAPRO-2 study tested the combination of two medicines called talazoparib plus enzalutamide. This combination of medicines was used as the first treatment for adult patients with metastatic castration-resistant prostate cancer.

Clinical Trial Protocol for VIOLET: A Single-Center, Phase I/II Trial Evaluation of Radioligand Treatment in Patients with Metastatic Castration-Resistant Prostate Cancer with [Tb]Tb-PSMA-I&T.

[Lu]Lu-PSMA is an effective class of therapy for patients with metastatic castration-resistant prostate cancer (mCRPC); however, progression is inevitable. The limited durability of response may be partially explained by the presence of micrometastatic deposits, which are energy-sheltered and receive low absorbed radiation with Lu due to the approximately 0.7-mm mean pathlength.

Precision medicine for prostate cancer: An international perspective.

Greater personalization of cancer medicine continues to shape therapy development and patient selection accordingly. The treatment of prostate cancer has evolved considerably since the discovery of androgen deprivation therapy. The comprehensive profiling of the prostate cancer genome has mapped the targetable molecular landscape of the disease and identified opportunities for the implementation of novel and combination therapies.

Validation of Prognostic and Predictive Models for Therapeutic Response in Patients Treated with [Lu]Lu-PSMA-617 Versus Cabazitaxel for Metastatic Castration-resistant Prostate Cancer (TheraP): A Post Hoc Analysis from a Randomised, Open-label, Phase 2 Trial.

Background: Prognostic models have been developed using data from a multicentre noncomparative study to forecast the likelihood of a 50% reduction in prostate-specific antigen (PSA50), longer prostate-specific antigen (PSA) progression-free survival (PFS), and longer overall survival (OS) in patients with metastatic castration-resistant prostate cancer receiving [Lu]Lu-PSMA radioligand therapy. The predictive utility of the models to identify patients likely to benefit most from [Lu]Lu-PSMA compared with standard chemotherapy has not been established.

Objective: To determine the predictive value of the models using data from the randomised, open-label, phase 2, TheraP trial (primary objective) and to evaluate the clinical net benefit of the PSA50 model (secondary objective).

Low rate of severe-end-stage kidney disease after SABR for localised primary kidney cancer.

Background: Stereotactic ablative body radiotherapy (SABR) is an emerging treatment for patients with primary renal cell carcinoma (RCC). However, its impact on renal function is unclear. This study aimed to evaluate incidence and clinical factors predictive of severe to end-stage chronic kidney disease (CKD) after SABR for RCC.

Clinical Outcomes of Enzalutamide in Metastatic Hormone-sensitive Prostate Cancer in Patients Aged <75 and ≥75 Years: ARCHES Post Hoc Analysis.

Background: In ARCHES, treatment intensification of androgen deprivation therapy (ADT) with enzalutamide versus placebo improved clinical outcomes in metastatic hormone-sensitive prostate cancer (mHSPC). Understanding the benefits and tolerability of enzalutamide for men aged ≥75 yr may inform disease management.

Objective: To determine whether age is associated with clinical outcomes in mHSPC.

Cost Effectiveness of Systemic Treatment Intensification for Metastatic Hormone-sensitive Prostate Cancer: Is Triplet Therapy Cost Effective?

Background And Objective: There has been a shift toward systemic treatment intensification for men with metastatic hormone-sensitive prostate cancer (mHSPC). Recent trials have demonstrated the efficacy of triplet therapy with an androgen receptor signalling inhibitor (ARSI), docetaxel, and androgen deprivation therapy (ADT). However, ARSI treatment is expensive.

Overall survival with [Lu]Lu-PSMA-617 versus cabazitaxel in metastatic castration-resistant prostate cancer (TheraP): secondary outcomes of a randomised, open-label, phase 2 trial.

Background: The TheraP study reported improved prostate-specific antigen responses with lutetium-177 [Lu]Lu-PSMA-617 versus cabazitaxel in men with metastatic castration-resistant prostate cancer progressing after docetaxel. In this Article, we report the secondary outcome of overall survival with mature follow-up, and an updated imaging biomarker analysis. We also report the outcomes of participants excluded due to ineligibility on gallium-68 [Ga]Ga-PSMA-11 and 2-[F]fluoro-2-deoxy-D-glucose (2-[F]FDG) PET-CT.