Activity of Lutetium-177 Prostate-specific Membrane Antigen and Determinants of Outcomes in Patients with Metastatic Castration-resistant Prostate Cancer Previously Treated with Cabazitaxel: The PACAP Study.

BACKGROUND: Both cabazitaxel and lutetium-177 prostate-specific membrane antigen (Lu-PSMA) improve survival in metastatic castration-resistant prostate cancer (mCRPC) after an androgen receptor pathway inhibitor and docetaxel, but there are limited data regarding Lu-PSMA activity after cabazitaxel. OBJECTIVE: To assess the activity of Lu-PSMA and determinants of outcomes after cabazitaxel in mCRPC. DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis was conducted of consecutive mCRPC patients from eight European centers treated with Lu-PSMA after cabazitaxel. INTERVENTION: Lu-PSMA every 6-8 wk at a dose of 6-7.6 GBq. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was radiographic progression-free survival (rPFS). The secondary endpoints included time to prostate-specific antigen (PSA) progression (TTPSA), overall survival (OS), PSA decline, objective response rate (ORR), clinical benefit, and safety. RESULTS AND LIMITATIONS: Of 126 patients, 68% had International Society of Urological Pathology (ISUP) grade 4-5 disease, 21% had visceral metastases, and 7% had lymph node disease only. DNA damage repair (DDR) alterations were detected in 11/50 (22%) patients with available testing. Patients received a median number of 3 Lu-PSMA cycles (interquartile range 2-4). With a median follow-up of 12.0 mo, the median rPFS was 4.4 mo (95% confidence interval [CI] 3.2-5.4), TTPSA 3.5 mo (95% CI 3.0-4.6), and OS 8.9 mo (95% CI 6.5-12.7). The ORR was 35%, and 55 patients (44%) experienced a PSA decline of ≥50%. The time to castration resistance of <12 mo was associated with shorter rPFS (p = 0.01). A similar trend was observed for ISUP grade 4-5 (p = 0.08), and baseline positron-emission tomography parameters including PSMA mean standardized uptake value (SUV) and maximum SUV (respectively, p = 0.06 and 0.05). The duration of previous cabazitaxel or DDR status did not impact outcomes. Patients experiencing a PSA decline of ≥ 50% on therapy demonstrated longer rPFS, TTPSA, and OS (all p < 0.0001). Limitations include retrospective data collection and investigator-based rPFS assessment. CONCLUSIONS: Lu-PSMA demonstrated a substantial PSA decline but limited rPFS after cabazitaxel in a real-life setting. Adverse baseline characteristics, baseline positron-emission tomography parameters, and quality of PSA response may help identify patients less likely to benefit from Lu-PSMA. PATIENT SUMMARY: Lutetium-177 prostate-specific membrane antigen (Lu-PSMA) improved outcomes in patients with castration-resistant prostate cancer, but there are limited data about its activity after cabazitaxel, a chemotherapy that is also the standard of care in this setting. We conducted a study across eight European centers and showed substantial responses on Lu-PSMA after cabazitaxel, although activity was short lived in a heavily pretreated population. Our findings prompt for real-life evaluation of Lu-PSMA in earlier settings to define the best therapeutic sequence.

B cells and the coordination of immune checkpoint inhibitor response in patients with solid tumors.

Immunotherapy profoundly changed the landscape of cancer therapy by providing long-lasting responses in subsets of patients and is now the standard of care in several solid tumor types. However, immunotherapy activity beyond conventional immune checkpoint inhibition is plateauing, and biomarkers are overall lacking to guide treatment selection. Most studies have focused on T cell engagement and response, but there is a growing evidence that B cells may be key players in the establishment of an organized immune response, notably through tertiary lymphoid structures. Mechanisms of B cell response include antibody-dependent cellular cytotoxicity and phagocytosis, promotion of CD4+ and CD8+ T cell activation, maintenance of antitumor immune memory. In several solid tumor types, higher levels of B cells, specific B cell subpopulations, or the presence of tertiary lymphoid structures have been associated with improved outcomes on immune checkpoint inhibitors. The fate of B cell subpopulations may be widely influenced by the cytokine milieu, with versatile roles for B-specific cytokines B cell activating factor and B cell attracting chemokine-1/CXCL13, and a master regulatory role for IL-10. Roles of B cell-specific immune checkpoints such as TIM-1 are emerging and could represent potential therapeutic targets. Overall, the expanding field of B cells in solid tumors of holds promise for the improvement of current immunotherapy strategies and patient selection.

Clinical utility of plasma ctDNA sequencing in metastatic urothelial cancer.

BACKGROUND: Genomic stratification may help improve the management of patients with metastatic urothelial cancer (mUC), given the recent identification of targetable alterations. However, the collection of tissue samples remains challenging. Here, we assessed the clinical utility of plasma circulating tumour DNA (ctDNA) sequencing in these patients. METHODS: Patients with mUC were prospectively enroled in the STING trial (NCT04932525), in which ctDNA was profiled using the Foundation One Liquid CDx Assay (324 genes, blood tumour mutational burden [bTMB], microsatellite instability status). Each genomic report was reviewed by a multidisciplinary tumor board (MTB). RESULTS: Between January 2021 and June 2022, 140 mUC patients underwent molecular profiling. The median time to obtain the assay results was 20 days ((confidence interval) CI95%: [20,21]). The ctDNA analysis reproduced the somatic genomic landscape of previous tissue-based cohorts. Concordance for serial ctDNA samples was strong (r = 0.843 CI95%: [0.631-0.938], p < 0.001). At least one actionable target was detected in 63 patients (45%) with a total of 35 actionable alterations, including bTMB high (≥10 mutations/Mb) (N = 39, 21.1%), FGFR3 (N = 20, 10.8%), and Homologous recombination deficiency (HRD) alterations (N = 14, 7.6%). MTB recommended matched therapy in 63 patients (45.0%). Eight patients (5.7%) were treated, with an overall response rate of 50% (CI95%: 15.70-84.30) and a median progression-free survival (PFS) of 5.2 months (CI95%: 4.1 - NR). FGFR3 alterations were associated with a shorter PFS in patients treated with immunotherapy. CONCLUSION: Overall, we demonstrated that genomic profiling with ctDNAs in mUC is a reliable and feasible approach for the timely initiation of genotype-matched therapies.

Risk Factors for Relapse in Nonseminomatous Testicular Cancer After Postchemotherapy Retroperitoneal Lymph Node Dissection With Viable Residual Cancer.

PURPOSE: No consensus exists on the management of men with nonseminoma and viable nonteratomatous germ cell tumor in the postchemotherapy retroperitoneal lymph node dissection (pcRPLND) specimen after first-line chemotherapy. We analyzed surveillance versus different adjuvant chemotherapy regimens and the influence of time to pcRPLND on oncologic outcomes. METHODS: Data on 117 men treated with cisplatin-based first-line chemotherapy between 1990 and 2018 were collected from 13 institutions. All patients had viable nonteratomatous germ cell tumor in the pcRPLND specimen. Surgery was performed after a median of 57 days, followed by either surveillance (n = 64) or adjuvant chemotherapy (n = 53). Primary end points were progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). RESULTS: After controlling for International Germ Cell Cancer Cooperative Group risk group and percent of viable malignant cells found at RPLND, no difference was observed between men managed with surveillance or adjuvant chemotherapy regarding PFS (hazard ratio [HR], 0.72 [95% CI, 0.32 to 1.6]; P = .4), CSS (HR, 0.69; 95% CI, 0.20 to 2.39; P = .6), and OS (HR, 0.78 [95% CI, 0.25 to 2.44]; P = .7). No statistically significant differences for PFS, CSS, or OS were observed on the basis of chemotherapy regimen or in men treated with pcRPLND ≤57 versus >57 days after first-line chemotherapy. Residual disease with <10% versus ≥10% viable cancer cells were associated with a longer PFS (HR, 3.22 [95% CI, 1.29 to 8]; P = .012). Relapse in the retroperitoneum was observed in 34 (29%) men. CONCLUSION: Men with a complete resection at pcRPLND and <10% viable cells have favorable outcomes without further treatment. Complete retroperitoneal resection seems more important than early pcRPLND.

Efficacy and safety of cabozantinib rechallenge in metastatic renal cell carcinoma: A retrospective multicentric study.

BACKGROUND: Despite metastatic renal cell carcinoma (mRCC) expanded treatment options, disease progression ultimately occurs for most patients. Rechallenge may be a compelling strategy in a refractory setting. Cabozantinib is the standard of care in first and later lines of therapy, but its activity in rechallenge is unknown. METHODS: This retrospective study assessed the efficacy and safety of cabozantinib rechallenge, as defined by a second exposure after an interval of ≥3 months without treatment or ≥1 other treatment line, in patients with mRCC. The primary endpoint was median progression-free survival (PFS) at rechallenge. Secondary endpoints included overall survival, objective response rate, and safety at rechallenge. RESULTS: We included 51 mRCC patients who received cabozantinib in a rechallenge setting between 2017 and 2022. Median age at diagnosis was 54 years, 78% were male, 90% had clear cell mRCC, and 92% had prior nephrectomy. 15 patients (29%) were rechallenged after a pause in treatment, whereas 36 (70.6%) had ≥1 other treatment lines between first cabozantinib exposure (CABO-1) and rechallenge (CABO-2). Median PFS was 15.1 months (mo, 95% Confidence interval 11.2-22.1) at CABO-1 and 14.4mo (95%CI 9.8-NR) at CABO-2. Median overall survival was 67.6mo for CABO-1 (95% CI 52.2-NR) and 27.4mo for CABO-2 (95%CI 17.2-NR); objective response rate was 70.6% for CABO-1 and 60% for CABO-2. CABO-2 PFS was higher for patients with CABO-1 PFS > 12 months, and for those who discontinued CABO-1 because of toxicity, without statistical significance. There were no unexpected adverse events. CONCLUSIONS: Cabozantinib rechallenge is a feasible treatment option with potential clinical benefit for mRCC patients.

Genomic Profiling of Metastatic Castration-Resistant Prostate Cancer Samples Resistant to Androgen Receptor Pathway Inhibitors.

PURPOSE: The androgen receptor axis inhibitors (ARPI; e.g., enzalutamide, abiraterone acetate) are administered in daily practice for men with metastatic castration-resistant prostate cancer (mCRPC). However, not all patients respond, and mechanisms of both primary and acquired resistance remain largely unknown. EXPERIMENTAL DESIGN: In the prospective trial MATCH-R (NCT02517892), 59 patients with mCRPC underwent whole-exome sequencing (WES) and/or RNA sequencing (RNA-seq) of samples collected before starting ARPI. Also, 18 patients with mCRPC underwent biopsy at time of resistance. The objectives were to identify genomic alterations associated with resistance to ARPIs as well as to describe clonal evolution. Associations of genomic and transcriptomic alterations with primary resistance were determined using Wilcoxon and Fisher exact tests. RESULTS: WES analysis indicated that no single-gene genomic alterations were strongly associated with primary resistance. RNA-seq analysis showed that androgen receptor (AR) gene alterations and expression levels were similar between responders and nonresponders. RNA-based pathway analysis found that patients with primary resistance had a higher Hedgehog pathway score, a lower AR pathway score and a lower NOTCH pathway score than patients with a response. Subclonal evolution and acquisition of new alterations in AR-related genes or neuroendocrine differentiation are associated with acquired resistance. ARPIs do not induce significant changes in the tumor transcriptome of most patients; however, programs associated with cell proliferation are enriched in resistant samples. CONCLUSIONS: Low AR activity, activation of stemness programs, and Hedgehog pathway were associated with primary ARPIs' resistance, whereas most acquired resistance was associated with subclonal evolution, AR-related events, and neuroendocrine differentiation. See related commentary by Slovin, p. 4323.

Stage II Seminoma: Why Chemotherapy Should Remain a Standard.

Chemotherapy (three cycles of bleomycin + etoposide + cisplatin or four of etoposide + cisplatin) cures the vast majority of stage II seminomas. Retroperitoneal lymph node dissection (RPLND) is safe in early-stage seminoma, but the risk of relapse is not negligible. Long-term chemotherapy side effects are a reality but may be reduced using de-escalation strategies such as in the SEMITEP trial design, motivated by growing interest in survivorship. RPLND may be an option for well-informed select patients who understand that it may be associated with a higher rate of relapse than with cisplatin-based chemotherapy. In any case, local and systemic treatment should not be performed outside high-volume centers.

Risk of residual cancer after complete response following first-line chemotherapy in men with metastatic non-seminomatous germ cell tumour and International Germ Cell Cancer Cooperative Group intermediate/poor prognosis: A multi-institutional retrospective cohort study.

INTRODUCTION: Current guidelines recommend surveillance in metastatic non-seminomatous germ cell tumour patients treated with first-line-chemotherapy and a complete clinical response (normalisation of serum tumour markers and residual masses <1 cm). However, this recommendation is based on a series including patients with good prognosis according to International Germ Cell Cancer Cooperative Group prognostic group (IGCCCG-PG). The aim of this study was to analyse the proportion of residual teratoma and survival among patients with intermediate/poor IGCCCG-PG and a complete clinical response after first-line-chemotherapy. MATERIAL & METHODS: This is a retrospective study of men with intermediate/poor IGCCCG-PG, who had a complete clinical response after first-line chemotherapy. Patients were either followed by surveillance or treated with post-chemotherapy retroperitoneal lymph node dissection (pcRPLND). RESULTS: Between 2009 and 2018, 143 men with intermediate (n = 83) or poor (n = 60) IGCCCG-PG were treated at 11 international centres. Among 33 patients treated with pcRPLND, the specimen showed teratoma and viable cancer in 16 (48%) and 4 (12%). During a median a 7-year follow-up, 20/110 (18%) patients managed with surveillance relapsed, of whom seven (6%) had a retroperitoneal-only relapse versus 2/33 patients managed with pcRPLND relapsed. No difference was observed regarding overall survival (OS) among men treated with pcRPLND or surveillance (5-year OS, 93% and 89%, p-value = 0.35). The median time-to-recurrence among men on surveillance was 1.3 years (range: 0.3-9.1), and the most common sites of relapses included retroperitoneum (11%), chest (5%), and bones (4%). CONCLUSIONS: While most men with intermediate/poor IGCCCG-PG harbour teratoma/cancer in the retroperitoneum despite a complete response to first-line-chemotherapy, only 6% managed with surveillance relapsed in the retroperitoneum. There was no significant difference in OS between the two groups.

Twitter as a Medical Media Among French Young Oncologists: Results from a National Survey.

Since its launch in 2006, Twitter has become a commonly used platform for sharing medical information, especially in the field of oncology. However, its role and impact on young oncologists' education remain unclear. Moreover, COVID-19 and congress virtualization is likely to have modified Twitter use by the medical society.We conducted a national survey (27 questions) in France among medical oncology, hematology, and radiation therapy young doctors to help better understand the role played by Twitter on their medical education. One hundred eighty-three young oncologists participated in our survey. A majority does not use Twitter (72.1%), mostly to reduce their time spent on social media. Participants using Twitter (27.9%) often use it more than once a week, mostly by scrolling on their news feed. Interestingly, they rarely express their own opinion on Twitter: a majority of them (75.5%) tweet less than once a month while the rest of them mostly retweet others' tweets. They mainly follow English-speaking experts, scientific societies, and medical journals. Pharmaceutical laboratories' accounts are of less significance. Overall Twitter usage seems increasing since COVID-19 pandemic and the consequent digitalization of congresses. No statistical difference was observed between the baseline characteristics of Twitter users and non-users.This survey shows that Twitter is a relevant mean of continuous medical education used by around a third of French young oncologists, especially since COVID-19 pandemic and the virtualization of congresses. This media should be considered and evaluated for its educational advantages or potential biases.

Development of Novel Models of Aggressive Variants of Castration-resistant Prostate Cancer.

BACKGROUND: Genomic studies have identified new subsets of aggressive prostate cancer (PCa) with poor prognosis (eg, neuroendocrine prostate cancer [NEPC], PCa with DNA damage response [DDR] alterations, or PCa resistant to androgen receptor pathway inhibitors [ARPIs]). Development of novel therapies relies on the availability of relevant preclinical models. OBJECTIVE: To develop new preclinical models (patient-derived xenograft [PDX], PDX-derived organoid [PDXO], and patient-derived organoid [PDO]) representative of the most aggressive variants of PCa and to develop a new drug evaluation strategy. DESIGN, SETTING, AND PARTICIPANTS: NEPC (n = 5), DDR (n = 7), and microsatellite instability (MSI)-high (n = 1) PDXs were established from 51 patients with metastatic PCa; PDXOs (n = 16) and PDOs (n = 6) were developed to perform drug screening. Histopathology and treatment response were characterized. Molecular profiling was performed by whole-exome sequencing (WES; n = 13), RNA sequencing (RNA-seq; n = 13), and single-cell RNA-seq (n = 14). WES and RNA-seq data from patient tumors were compared with the models. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Relationships with outcome were analyzed using the multivariable chi-square test and the tumor growth inhibition test. RESULTS AND LIMITATIONS: Our PDXs captured both common and rare molecular phenotypes and their molecular drivers, including alterations of BRCA2, CDK12, MSI-high status, and NEPC. RNA-seq profiling demonstrated broad representation of PCa subtypes. Single-cell RNA-seq indicates that PDXs reproduce cellular and molecular intratumor heterogeneity. WES of matched patient tumors showed preservation of most genetic driver alterations. PDXOs and PDOs preserve drug sensitivity of the matched tissue and can be used to determine drug sensitivity. CONCLUSIONS: Our models reproduce the phenotypic and genomic features of both common and aggressive PCa variants and capture their molecular heterogeneity. Successfully developed aggressive-variant PCa preclinical models provide an important tool for predicting tumor response to anticancer therapy and studying resistance mechanisms. PATIENT SUMMARY: In this report, we looked at the outcomes of preclinical models from patients with metastatic prostate cancer enrolled in the MATCH-R trial (NCT02517892).

Evaluation of supportive care needs, sexuality and quality of life in phase 1 trials: a prospective monocentric study.

PURPOSE: Patients enrolled in oncology phase 1 trials (ph1) usually have advanced heavily pre-treated cancers with few therapeutic options. Quality of life (QoL) is one of the key cancer-treatment outcome measures, especially in ph1, and sexuality is an important part of Qol but rarely explored. This prospective study aims to assess supportive care needs, QoL and sexuality in ph1. METHODS: Between September 2020 and June 2021, we prospectively recruited patients enrolled in ph1 at Gustave Roussy in France. Supportive care needs, QoL (EORTC QLQ-C30) and sexuality (female sexual function index for women, male sexual health questionnaire [MSHQ] for men) were assessed at baseline, one, three and 5 months. We performed multivariate analyses to identify associations between clinical characteristics, QoL and quality of sexual life over time. RESULTS: At baseline, we analyzed 187 patients (45% women (n = 84) and 55% men (n = 103)). Patients expressed the need for consultations in pain management, nutrition, psychology and sexology in 28%, 26%, 19% and 9%, respectively. Lower global QoL was independently associated with Royal Marsden Hospital score (p = 0.012), urogenital location tumor (p = 0.021), elevated CRP levels (p = 0.014) and pain intensity (p = 0.005). Ninety-two percent of women had sexual dysfunction. In men, a lower MSHQ score was independently associated with urogenital location tumor (p = 0.021), ECOG Performance Status (p = 0.006), comorbidity at risk (p = 0.024) and pain intensity (p = 0.004). CONCLUSIONS: There are significant needs for supportive care in ph1, especially in some subgroups of patients. New models of care should be developed to improve early phase pathways.

The Role of CT in the Staging and Follow-Up of Testicular Tumors: Baseline, Recurrence and Pitfalls.

Ultrasound imaging of the testis represents the standard-of-care initial imaging for the diagnosis of TGCT, whereas computed tomography (CT) plays an integral role in the initial accurate disease staging (organ-confined, regional lymph nodes, or sites of distant metastases), in monitoring the response to therapy in patients who initially present with non-confined disease, in planning surgical approaches for residual masses, in conducting follow-up surveillance and in determining the extent of recurrence in patients who relapse after treatment completion. CT imaging has also an important place in diagnosing complications of treatments. The aims of this article are to review these different roles of CT in primary TGCT and focus on different pitfalls that radiologists need to be aware of.

[Formation of French oncology resident: A national survey]. / État des lieux de la formation initiale de l'internat d'oncologie après la quatrième vague pandémie de la COVID-19 : une enquête AERIO-SFJRO.

BACKGROUND: COVID-19 pandemic troubled hospital and university's organization. Previous study showed oncology resident's formation has been impacted by pandemic. One year later, we aimed to evaluate the state of oncology resident's formation. METHODS: We conducted a transversal study written by AERIO and SJRO, released via social networks and mail to the French oncology residents. RESULTS: One hundred and sixty-four residents answered. Sixty-four (39%) were male and 99 (60.4%) were female, mean age was 26.8 years old, mean semester was 5.7. One hundred and five (64%) were medical oncologist and 53 (32.3%) were radiation oncologist. One hundred and forty residents (85.4%) had lectures during hospital internships, mainly in cancer center (77.1%) and academic hospitals (60.7%). One hundred and twenty-one residents (73.8%) had specialized diploma lectures, in 34.7% of case monthly. Respectively 42.7% and 18.3% of residents could access to their formation's day respectively rarely and never. Strengths of oncology residency were scientific dynamism (91.9%), clinical breadth (82%) and knowledge renewal (78.9%). Attractivity's obstacles to the residency were psychological arduousness (64%), administrative burden (48.2%) and too important worktime (47%). CONCLUSION: This survey shows the state of play of French oncology residency's formation at the end of 2021.

PARP Inhibition, a New Therapeutic Avenue in Patients with Prostate Cancer.

Up to 25% of patients with metastatic prostate cancer present with germline or somatic DNA damage repair alterations, some of which are associated with aggressive disease and poor outcomes. New data have brought poly(ADP-ribose) polymerase (PARP) inhibitors into sharp focus in the treatment of metastatic castrate-resistant prostate cancer (mCRPC). Olaparib improved survival after at least one new hormonal therapy (NHT) in a cohort of patients harboring BRCA1, BRCA2 or ATM mutations in the PROfound trial, while rucaparib, talazoparib and niraparib demonstrated compelling activity in phase II trials. While patients with prostate cancer and BRCA1 or BRCA2 mutations may derive greatest benefit of PARP inhibition, the magnitude of benefit seems much lower in the context of most other homologous recombination gene mutations. Several PARP inhibitors are currently developed in combination with conventional therapy, including chemotherapy, NHT, and alpha-particle emitters, at different disease stages. Herein, we review the rationale for PARP inhibition in patients with prostate cancer, discuss the impact of PARP inhibitors on outcomes, and explore underlying challenges for future developments.

[Goals, motivations, and difficulties of young oncology residents]. / Objectifs, motivations et difficultés des internes en phase socle en oncologie.

INTRODUCTION: The Association for education and research of interns in oncology (AERIO) conducted a national survey of the 2020-year oncology residents promotion in the "phase socle". The objective was to collect and analyze their motivations, as well as the objectives and limitations in the life and career of the residents during this first year of residency. METHODS: A questionnaire included 45 closed questions divided into 6 sections describing: the demographic characteristics of the population, the commitment of the students' and their clinical and academic expectations in the, their training, their life and career objectives, and their commitment in associative life. RESULTS: Seventy-eight of 119 residents participated (66%), of which 68 (87.2%) completed the questionnaire entirely. The population was predominantly women (60%) with a median age of 24 years. The choice between medical or radiation oncology was mostly undefined (87%) and 15% of the residents considered to change their medical specialty. The average hospital work time reported was predominantly between 45 and 65hours per week (83%). Sixty-nine percent were primarily interested in clinical research. One out of two residents (52%) did not have access to their half-day of training per week. DISCUSSION: This national survey made possible to analyze the perception of oncology young residents, as well as their career aspirations and their relationship to research.