Much ado about nothing? Assessing the actual benefits of proton beam therapy for prostate cancer.

We are discussing and commenting on the paper by Yu et al. titled "Updated Analysis of Comparative Toxicity of Proton and Photon Radiation for Prostate Cancer," published in the Journal of Clinical Oncology in June 2024.

Innovative On-Resin and in Solution Peptidomimetics Synthesis via Metal-Free Photocatalytic Approach.

Nowadays, peptidomimetics are widely studied, being useful tools in drug discovery and medicinal chemistry. The coupling between a carboxylic acid with an amine to form a peptide bond is the most common reaction to obtain peptides/peptidomimetics. In this work, we have investigated an innovative metal-free photoredox-catalyzed carbamoylation to form peptidomimetics thanks to the reaction between dihydropyridines functionalized with amino acids (or peptide sequences) and differently functionalized imines. As the organic photocatalyst, we used 4CzIPN, a donor-acceptor cyanoarene vastly used in photoredox catalysis. By easily modulating the amino acid (or peptide sequence), which is directly attached to the dihydropyridine, we proposed this key-reaction as new valuable method to obtain peptidomimetics, in situ building the not-natural portion of the sequence. Moreover, we successfully employed this methodology in solid phase peptide synthesis, both inserting the new photoredox-generated amino acid at the end or in the middle of the sequence. Peptides with different lengths and secondary structures were prepared, proving the success of this approach, even in sterically hindered environment. Herein, to the best of our knowledge, we describe the first photocatalytic protocol which allows the building of the peptide backbone, with the possibility of simultaneously inserting a non-coded amino acid in the sequence.

Local Treatment (Primary Tumor and Metastases) in Metastatic Prostate Cancer.

For patients with low-volume de novo metastatic hormone-sensitive prostate cancer, addition of an androgen receptor pathway inhibitor and prostate radiotherapy to the standard (SOC) improves survival in comparison to the next most effective strategy (SOC + ARPI). For the subgroup with prior definitive treatment of the primary tumor, long-term outcomes and genomic predictors of response to metastasis-directed therapy suggest that this might be a reasonable option in selected patients.

Seeding the vertical growth of laterally coherent coordination polymers on the rutile-TiO2(110) surface.

Coordination polymers may be synthesized by linear bridging ligands to metal ions with conventional chemistry methods (e.g. in solution). Such complexes can be hardly brought onto a substrate with the chemical, spatial and geometrical homogeneity required for device integration. Instead, we follow an in situ synthesis approach, where the anchoring points are provided by a monolayer of metal(II)-tetraphenylporphyrin (M-TPP, M = Cu, Zn, Co) grown in vacuum on the rutile-TiO2(110) surface. We probed the metal affinity to axial coordination by further deposition of symmetric dipyridyl-naphthalenediimide (DPNDI). By NEXAFS linear polarization dichroism, we show that DPNDI stands up on Zn- and Co-TPP thanks to axial coordination, whereas it lies down on the substrate for Cu-TPP. Calculations for a model pyridine ligand predict strong binding to Zn and Co cations, whose interaction with the O anions underneath is disrupted by surface trans effect. The weaker interactions between pyridine and Cu-TPP are then overcome by the strong attraction between TiO2 and DPNDI. The binding sites exposed by the homeotropic alignment of the ditopic DPNDI ligand on Zn- and Co-TPP are the foundations to grow coordination polymers preserving the lateral coherence of the basal layer.

Risk Stratification of Patients with Recurrence After Primary Treatment for Prostate Cancer: A Systematic Review.

BACKGROUND AND OBJECTIVE: Biochemical recurrence (BCR) after primary definitive treatment for prostate cancer (PCa) is a heterogeneous disease state. While BCR is associated with worse oncologic outcomes, risk factors that impact outcomes can vary significantly, necessitating avenues for risk stratification. We sought to identify prognostic risk factors at the time of recurrence after primary radical prostatectomy or radiotherapy, and prior to salvage treatment(s), associated with adverse oncologic outcomes. METHODS: We performed a systematic review of prospective studies in EMBASE, MEDLINE, and ClinicalTrials.gov (from January 1, 2000 to October 16, 2023) according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines (CRD42023466330). We reviewed the factors associated with oncologic outcomes among patients with BCR after primary definitive treatment. KEY FINDINGS AND LIMITATIONS: A total of 37 studies were included (total n = 10 632), 25 after prostatectomy (total n = 9010) and 12 after radiotherapy (total n = 1622). Following recurrence after prostatectomy, factors associated with adverse outcomes include higher pathologic T stage and grade group, negative surgical margins, shorter prostate-specific antigen doubling time (PSADT), higher prostate-specific antigen (PSA) prior to salvage treatment, shorter time to recurrence, the 22-gene tumor RNA signature, and recurrence location on molecular imaging. After recurrence following radiotherapy, factors associated with adverse outcomes include a shorter time to recurrence, and shorter PSADT or higher PSA velocity. Grade group, T stage, and prior short-term hormone therapy (4-6 mo) were not clearly associated with adverse outcomes, although sample size and follow-up were generally limited compared with postprostatectomy data. CONCLUSIONS AND CLINICAL IMPLICATIONS: This work highlights the recommendations and level of evidence for risk stratifying patients with PCa recurrence, and can be used as a benchmark for personalizing salvage treatment based on prognostics.

Efficacy and Safety of Radiotherapy Plus Relugolix in Men With Localized or Advanced Prostate Cancer.

Importance: Combination androgen deprivation therapy (ADT) with radiotherapy is commonly used for patients with localized and advanced prostate cancer. Objective: To assess the efficacy and safety of the oral gonadotropin-releasing hormone antagonist relugolix with radiotherapy for treating prostate cancer. Design, Setting, and Participants: This multicenter post hoc analysis of patients with localized and advanced prostate cancer receiving radiotherapy in 2 randomized clinical trials (a phase 2 trial of relugolix vs degarelix, and a subset of the phase 3 HERO trial of relugolix vs leuprolide acetate) included men who were receiving radiotherapy and short-term (24 weeks) ADT (n = 103) from 2014 to 2015 and men receiving radiotherapy and longer-term (48 weeks) ADT (n = 157) from 2017 to 2019. The data were analyzed in November 2022. Interventions: Patients receiving short-term ADT received relugolix, 120 mg, orally once daily (320-mg loading dose) or degarelix, 80 mg, 4-week depot (240-mg loading dose) for 24 weeks with 12 weeks of follow-up. Patients receiving longer-term ADT received relugolix, 120 mg, orally once daily (360-mg loading dose) or leuprolide acetate injections every 12 weeks for 48 weeks, with up to 90 days of follow-up. Main Outcomes and Measures: Castration rate (testosterone level <50 ng/dL [to convert to nmol/L, multiply by 0.0347) at all scheduled visits between weeks 5 and 25 for patients receiving short-term ADT and weeks 5 and 49 for patients receiving longer-term ADT. Results: Of 260 patients (38 Asian [14.6%], 23 Black or African American [8.8%], 21 Hispanic [8.1%], and 188 White [72.3%] individuals), 164 (63.1%) received relugolix. Relugolix achieved castration rates of 95% (95% CI, 87.1%-99.0%) and 97% (95% CI, 90.6%-99.0%) among patients receiving short-term and longer-term ADT, respectively. Twelve weeks post-short-term relugolix, 34 (52%) achieved testosterone levels to baseline or more than 280 ng/dL. Ninety days post longer-term ADT, mean (SD) testosterone levels were 310.5 (122.4) (106.7) ng/dL (relugolix; n = 15) vs 53.0 ng/dL (leuprolide acetate; n = 8) among the subset assessed for testosterone recovery. Castration resistance-free survival was not statistically different between the relugolix and leuprolide acetate cohorts (hazard ratio, 0.97; 95% CI, 0.35-2.72; P = .62). Adverse events grade 3 or greater for short-term or longer-term relugolix (headache, hypertension, and atrial fibrillation) were uncommon (less than 5%). Conclusions and Relevance: The results of these 2 randomized clinical trials suggest that relugolix rapidly achieves sustained castration in patients with localized and advanced prostate cancer receiving radiotherapy. No new safety concerns were identified when relugolix was used with radiotherapy.

ProtecT trial: What's new after 15 years of follow-up: Re: Hamdy FC and colleagues; N Engl J Med. 2023 Apr 27.

Recent results of ProtecT trial published after 15 years of follow-up demonstrate the absence of difference in prostate cancer-specific survival between active monitoring, radiotherapy, or prostatectomy for PSA-detected, localized prostate cancer patients. These results definitively confirm the essential role of active surveillance as the gold standard for men with low-risk and highly selected intermediate-risk prostate cancer. It underlines the importance of shared-decision making process with patients.

Aggregation-Induced Enhanced Emission of Tetraphenylethene-phenylalanine Hybrids: Synthesis and Characterization.

Aggregation-induced emitting (AIE) luminophores are sensitive and easy-to-handle types of probes that allow driving a stimulus-responsive off/on optical tool through the manipulation of the aggregation behavior. In this work, tetraphenylethene (TPE)-phenylalanine derivatives, characterized by strong aggregation-induced luminescence, were obtained through Suzuki-Miyaura cross-coupling reactions. The reaction proved to be straightforwardly applicable in the single amino acid synthesis as well as in the late-stage peptide functionalization by means of both the classical solution-phase reaction and solid-phase synthesis. A comprehensive structural and analytical investigation highlighted the features driving the self-assembly process and its relationship to AIE efficiency. In particular, we showed that the simple slight (asymmetric) extension of the TPE π-systems results in more efficient and brighter emissions, with respect to the simple TPE system itself.

Relugolix vs. Leuprolide Effects on Castration Resistance-Free Survival from the Phase 3 HERO Study in Men with Advanced Prostate Cancer.

Background: Relugolix is an oral GnRH receptor antagonist approved for men with advanced prostate cancer. Relugolix treatment has demonstrated an ability to lower testosterone to sustained castration levels in the phase 4 HERO study. Herein, we describe the results of a secondary endpoint of castration resistance-free survival (CRFS) during 48 weeks of treatment and profile patients with castration-resistant prostate cancer (CRPC). Methods: Subjects were 2:1 randomized to either relugolix 120 mg orally once daily (after a single 360 mg loading dose) or 3-monthly injections of leuprolide for 48 weeks. CRFS, defined as the time from the date of first dose to the date of confirmed prostate-specific antigen progression while castrated or death due to any reason was conducted in the metastatic disease population and the overall modified intention-to-treat (mITT) populations. Results: The CRFS analysis (mITT population) included 1074 men (relugolix: n = 717; leuprolide: n = 357) with advanced prostate cancer as well as 434 men (relugolix: n = 290; leuprolide: n = 144) with metastatic prostate cancer. In the metastatic disease populations, CRFS rates were 74.3% (95% CI: 68.6%, 79.2%) and 75.3% (95% CI: 66.7%, 81.9%) in the relugolix and leuprolide groups, respectively (hazard ratio: 1.03 [0.68, 1.57]; p = 0.84) at week 48. Results in the overall mITT population were similar to the metastatic population. No new safety findings were identified. Conclusions: In men with metastatic disease or in the overall population of the HERO study, CRFS assessed during the 48-week treatment with relugolix was not significantly different than standard-of-care leuprolide. Relugolix had similar efficacy for men with/without CRFS progression events.

Tetraphenylethylene-Based Photoluminescent Self-Assembled Nanoparticles: Preparation and Biological Evaluation.

The conjugation of tetraphenylethylene (TPE) with podophyllotoxin, N-desacetylthiocolchicine, and cabazitaxel through a sebacic acid linker led to the formation of fluorescent nanoparticles. Dynamic light scattering (DLS) and photoluminescence spectroscopy were used for the identification and characterization of the fluorescent nanoparticles. The biological evaluation was determined in three human ovarian (KURAMOCHI, OVCAR3, OVSAHO) and three human breast (MCF7, SKBR 3, and MDA-MB231) cancer cell lines. In the case of cabazitaxel, the nanoparticles maintained the activity of the parent drug, at the low nanomolar range, while exhibiting high blue fluorescence. The internalization of the fluorescent NPs into cells was detected using immunofluorescence assay.

Impact of Relugolix Versus Leuprolide on the Quality of Life of Men with Advanced Prostate Cancer: Results from the Phase 3 HERO Study.

BACKGROUND: Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, demonstrated testosterone suppression to castrate levels in men with advanced prostate cancer (PCa) in the HERO study. Since advanced PCa and its treatments can impact patients' daily life, it is imperative to understand the impact of systemic therapy on patient health-related quality of life (HRQOL). OBJECTIVE: To report the HRQOL for patients on relugolix compared with those on leuprolide in on-treatment and testosterone recovery periods of the HERO study. DESIGN, SETTING, AND PARTICIPANTS: A phase 3 randomized controlled study was conducted in 934 patients with advanced PCa. INTERVENTION: Patients underwent 2:1 randomization and received relugolix 120 mg orally once daily or leuprolide 3-mo injections for 48 wk. Testosterone recovery was evaluated in a patient subset. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: HRQOL evaluations were based on the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC QLQ-C30) and the Prostate Cancer Module (EORTC QLQ-PR25) during treatment and testosterone recovery phases. In a post hoc analysis, predictors of HRQOL deterioration were evaluated. RESULTS AND LIMITATIONS: No statistically significant differences between the two groups were found in changes from baseline to the end of treatment in either the EORTC QLQ-C30 or the EORTC QLQ-PR25 instrument. During the testosterone recovery phase, hormonal treatment-related symptoms scores were lower for relugolix than for leuprolide, suggesting a lower burden of hormone-related symptoms associated with a treatment that has more rapid testosterone recovery after treatment cessation. Limitations include low patient numbers in the testosterone recovery group. CONCLUSIONS: Oral relugolix is a therapeutic option with similar patient-reported HRQOL to leuprolide, providing an oral option for androgen deprivation therapy associated with a more rapid testosterone reduction. PATIENT SUMMARY: In men with advanced prostate cancer, relugolix had similar health-related quality of life to leuprolide.

ESTRO ACROP consensus recommendation on the target volume definition for radiation therapy of macroscopic prostate cancer recurrences after radical prostatectomy.

Background: The European Society for Radiotherapy & Oncology (ESTRO) Advisory Committee for Radiation Oncology Practice (ACROP) panel on prostate bed delineation reflected on macroscopic local recurrences in patients referred for postoperative radiotherapy (PORT), a challenging situation without standardized approach, and decided to propose a consensus recommendation on target volume selection and definition. Methods: An ESTRO ACROP contouring consensus panel consisting of 12 radiation oncologists and one radiologist, all with subspecialty expertise in prostate cancer, was established. Participants were asked to delineate the prostate bed clinical target volumes (CTVs) in two separate clinically relevant scenarios: a local recurrence at the seminal vesicle bed and one apically at the level of the anastomosis. Both recurrences were prostate-specific membrane antigen (PSMA)-avid and had an anatomical correlate on magnetic resonance imaging (MRI). Participants also answered case-specific questionnaires addressing detailed recommendations on target delineation. Discussions via electronic mails and videoconferences for final editing and consensus were performed. Results: Contouring of the two cases confirmed considerable variation among the panelists. Finally, however, a consensus recommendation could be agreed upon. Firstly, it was proposed to always delineate the entire prostate bed as clinical target volume and not the local recurrence alone. The panel judged the risk of further microscopic disease outside of the visible recurrence too high to safely exclude the rest of the prostate bed from the CTV. A focused, "stereotactic" approach should be reserved for re-irradiation after previous PORT. Secondly, the option of a focal boost on the recurrence was discussed. Conclusion: Radiation oncologists are increasingly confronted with macroscopic local recurrences visible on imaging in patients referred for postoperative radiotherapy. It was recommended to always delineate and irradiate the entire prostate bed, and not the local recurrence alone, whatever the exact location of that recurrence. Secondly, specific dose-escalation on the macroscopic recurrence should only be considered if an anatomic correlate is visible. Such a focal boost is probably feasible, provided that OAR constraints are prioritized. Possible dose is also dependent on the location of the recurrence. Its potential benefit should urgently be investigated in prospective clinical trials.

Visible Light-Promoted ß-Functionalization of Carbonyl Compounds in the Presence of Organic Dyes.

Herein, we investigate the use of organic photocatalysts in the visible light-promoted ß-functionalization of carbonyl compounds. In particular, we studied the addition of aliphatic aldehydes to α,ß-unsaturated compounds (ß-Michael addition), and the reaction of cyclic ketones with either ketones (ß-aldol condensation) or imines (ß-Mannich reaction). Among the dyes tested, donor-acceptor cyanoarenes gave the best results, promoting the transformations of interest in moderate to good yields. The reaction scope was investigated on substrates with different steric and electronic properties. Fluorescence quenching analysis (Stern-Volmer experiments) led us to propose for these reactions a reductive quenching mechanism involving a transient 5πe- activation mode.

The importance of anchoring ligands of binuclear sensitizers on electron transfer processes and photovoltaic action in dye-sensitized solar cells.

The relatively low photon-to-current conversion efficiency of dye-sensitized solar cells is their major drawback limiting widespread application. Light harvesting, followed by a series of electron transfer processes, is the critical step in photocurrent generation. An in-depth understanding and fine optimization of those processes are crucial to enhance cell performance. In this work, we synthesize two new bi-ruthenium sensitizers with extended anchoring ligands to gain insight into underlying processes determining photovoltaic action mechanisms. The structure of the compounds has been confirmed, and their properties have been thoroughly examined by various techniques such as NMR, IR, elemental analysis UV-Vis, cyclic voltammetry, and electroabsorption. The experimental characterization has been supported and developed via extensive quantum-chemical calculations, giving a broad view of the presented molecules' properties. Finally, the DSSC devices have been assembled utilizing obtained dyes. The photovoltaic and EIS measurements, combined with performed calculations and fundamental dyes characterization, unraveled an intramolecular electron transfer as an initial step of the electron injection process at the dye/semiconductor interface. The overall photovoltaic action mechanism has been discussed. Our study demonstrates the significance of the anchoring group architecture in the molecular design of new sensitizers for DSSC applications.

ESTRO ACROP guideline on prostate bed delineation for postoperative radiotherapy in prostate cancer.

Purpose/Objective: Radiotherapy to the prostate bed is a potentially curative salvage option after radical prostatectomy. Although prostate bed contouring guidelines are available in the literature, important variabilities exist. The objective of this work is to provide a contemporary consensus guideline for prostate bed delineation for postoperative radiotherapy. Methods: An ESTRO-ACROP contouring consensus panel consisting of 11 radiation oncologists and one radiologist, all with known subspecialty expertise in prostate cancer, was established. Participants were asked to delineate the prostate bed clinical target volumes (CTVs) in 3 separate clinically relevant scenarios: adjuvant radiation, salvage radiation with PSA progression, and salvage radiation with persistently elevated PSA. These cases focused on the presence of positive surgical margin, extracapsular extension, and seminal vesicles involvement. None of the cases had radiographic evidence of local recurrence on imaging. A single computed tomography (CT) dataset was shared via FALCON platform and contours were performed using EduCaseTM software. Contours were analyzed qualitatively using heatmaps which provided a visual assessment of controversial regions and quantitatively analyzed using Sorensen-Dice similarity coefficients. Participants also answered case-specific questionnaires addressing detailed recommendations on target delineation. Discussions via electronic mails and videoconferences for final editing and consensus were performed. Results: The mean CTV for the adjuvant case was 76 cc (SD = 26.6), salvage radiation with PSA progression was 51.80 cc (SD = 22.7), and salvage radiation with persistently elevated PSA 57.63 cc (SD = 25.2). Compared to the median, the mean Sorensen-Dice similarity coefficient for the adjuvant case was 0.60 (SD 0.10), salvage radiation with PSA progression was 0.58 (SD = 0.12), and salvage radiation with persistently elevated PSA 0.60 (SD = 0.11). A heatmap for each clinical scenario was generated. The group agreed to proceed with a uniform recommendation for all cases, independent of the radiotherapy timing. Several controversial areas of the prostate bed CTV were identified based on both heatmaps and questionnaires. This formed the basis for discussions via videoconferences where the panel achieved consensus on the prostate bed CTV to be used as a novel guideline for postoperative prostate cancer radiotherapy. Conclusion: Variability was observed in a group formed by experienced genitourinary radiation oncologists and a radiologist. A single contemporary ESTRO-ACROP consensus guideline was developed to address areas of dissonance and improve consistency in prostate bed delineation, independent of the indication.There is important variability in existing contouring guidelines for postoperative prostate bed (PB) radiotherapy (RT) after radical prostatectomy. This work aimed at providing a contemporary consensus guideline for PB delineation. An ESTRO ACROP consensus panel including radiation oncologists and a radiologist, all with known subspecialty expertise in prostate cancer, delineated the PB CTV in 3 scenarios: adjuvant RT, salvage RT with PSA progression, and salvage RT with persistently elevated PSA. None of the cases had evidence of local recurrence. Contours were analysed qualitatively using heatmaps for visual assessment of controversial regions and quantitatively using Sorensen-Dice coefficient. Case-specific questionnaires were also discussed via e-mails and videoconferences for consensus. Several controversial areas of the PB CTV were identified based on both heatmaps and questionnaires. This formed the basis for discussions via videoconferences. Finally, a contemporary ESTRO-ACROP consensus guideline was developed to address areas of dissonance and improve consistency in PB delineation, independent of the indication.

Management of patients with advanced prostate cancer-metastatic and/or castration-resistant prostate cancer: Report of the Advanced Prostate Cancer Consensus Conference (APCCC) 2022.

BACKGROUND: 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. OBJECTIVE: To present the voting results of the APCCC 2022. DESIGN, SETTING, AND PARTICIPANTS: 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. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: 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. RESULTS AND LIMITATIONS: 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. CONCLUSIONS: 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. PATIENT SUMMARY: 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. TWITTER SUMMARY: Report of the results of APCCC 2022 for the following topics: mHSPC, nmCRPC, mCRPC, and oligometastatic prostate cancer. TAKE-HOME MESSAGE: 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.

Impact of Concomitant Prostate Cancer Medications on Efficacy and Safety of Relugolix Versus Leuprolide in Men With Advanced Prostate Cancer.

BACKGROUND: To characterize the impact of concomitant prostate cancer treatments with the use of relugolix, the oral GnRH receptor antagonist, in advanced prostate cancer, a subgroup and pharmacokinetic/pharmacodynamic analyses of the HERO study was undertaken. PATIENTS AND METHODS: Overall, 934 patients were randomized 2:1 to receive relugolix 120 mg orally once daily or leuprolide injections every 12 weeks for 48 weeks. In the setting of rising PSA, patients could receive enzalutamide or docetaxel 2 months after study initiation. Assessments included sustained testosterone suppression to castrate levels (<50 ng/dL) through 48 weeks and safety parameters. Subgroups analyzed included patients with or without concomitant enzalutamide or docetaxel. A sensitivity analysis of the primary endpoint was performed excluding patients who received concomitant therapies that may affect testosterone. Pharmacokinetic/pharmacodynamic analyses of 20 participants in the relugolix treatment group assessed the net effect of enzalutamide on exposure to relugolix. RESULTS: Overall, 125 patients (13.4%) took concomitant therapies that could impact testosterone levels. Enzalutamide (n = 23) was the most frequently used therapy in the relugolix (2.7%) and leuprolide groups (1.9%). Docetaxel (n = 13) was used by 1.3% and 1.6% of patients in the relugolix and leuprolide groups, respectively. All other relevant concomitant therapy were used in <1% of population. Sensitivity analysis showed concomitant therapy did not impact the testosterone levels. Castration rates were similar with and without concomitant use of enzalutamide or docetaxel. No clinically relevant differences in adverse events were observed between subgroups in either treatment group. No differences in relugolix Ctrough or testosterone concentrations were observed, suggesting that any induction or inhibition properties of enzalutamide on relugolix metabolism result in a neutral net effect on relugolix exposure and testosterone suppression. CONCLUSION: Treatment with relugolix was associated with similar efficacy and safety profiles with and without concomitant enzalutamide or docetaxel. Standard-of-care use of relugolix in combination with these agents is supported by these data.