Predictors of long-term progression-free survival in patients with ovarian cancer treated with niraparib in the PRIMA/ENGOT-OV26/GOG-3012 study.

OBJECTIVE: To identify characteristics associated with long-term progression-free survival (≥2 years) in patients with advanced ovarian cancer treated with niraparib first-line maintenance therapy in the phase III PRIMA/ENGOT-OV26/GOG-3012 study. METHODS: In this post hoc analysis of PRIMA, patients randomized to niraparib were grouped based on investigator-assessed progression-free survival (progressive disease/censoring <2 years or ≥2 years after randomization). Variables assessed for predictive value were Eastern Cooperative Oncology Group performance status, International Federation of Gynecology and Obstetrics (FIGO) stage at diagnosis, clinical response to platinum-based chemotherapy, number of prior chemotherapy cycles, primary tumor location, body mass index, categorical age, debulking surgery type, number of baseline target lesions, number of baseline non-target lesions, BRCA/homologous recombination-deficiency status, residual disease status, and duration from end of chemotherapy to randomization. Logistic regression modeling using backward elimination (significance level=0.15) identified covariates associated with long-term progression-free survival (clinical cut-off date November 17, 2021). RESULTS: Of 487 patients randomized to niraparib, 152 (31%) had progressive disease/censoring ≥2 years after randomization. Multivariable logistic regression modeling using backward elimination identified BRCA1/2 mutation/homologous recombination deficiency status (p<0.0001), FIGO stage (p=0.041), primary tumor location (p=0.095), and number of baseline non-target lesions (p=0.0001) to be associated with long-term progression-free survival. Patients significantly more likely to achieve progression-free survival of ≥2 years in the final model were those with BRCA1- and BRCA2-mutated/homologous recombination-deficient tumors or BRCA wild-type/not determined/homologous recombination-deficient tumors (vs BRCA wild-type/homologous recombination-proficient/not determined tumors), FIGO stage III (vs IV), and 0 or 1 baseline non-target lesions (vs ≥2 baseline non-target lesions). CONCLUSIONS: The hypothesis-generating results of this analysis suggest that BRCA1/2 mutation/homologous recombination-deficiency status, FIGO stage, and number of baseline non-target lesions may predict progression-free survival of ≥2 years in patients with advanced ovarian cancer receiving niraparib first-line maintenance therapy. TRIAL REGISTRATION NUMBER: NCT02655016.

Homologous Recombination Repair Deficiency in Metastatic Prostate Cancer: New Therapeutic Opportunities.

More than 20% of metastatic prostate cancer carries genomic defects involving DNA damage repair pathways, mainly in homologous recombination repair-related genes. The recent approval of olaparib has paved the way to precision medicine for the treatment of metastatic prostate cancer with PARP inhibitors in this subset of patients, especially in the case of BRCA1 or BRCA2 pathogenic/likely pathogenic variants. In face of this new therapeutic opportunity, many issues remain unsolved. This narrative review aims to describe the relationship between homologous recombination repair deficiency and prostate cancer, the techniques used to determine homologous recombination repair status in prostate cancer, the crosstalk between homologous recombination repair and the androgen receptor pathway, the current evidence on PARP inhibitors activity in metastatic prostate cancer also in homologous recombination repair-proficient tumors, as well as emerging mechanisms of resistance to PARP inhibitors. The possibility of combination therapies including a PARP inhibitor is an attractive option, and more robust data are awaited from ongoing phase II and phase III trials outlined in this manuscript.

Consensus statements and treatment algorithm to guide clinicians in the selection of maintenance therapy for patients with newly diagnosed, advanced ovarian carcinoma: Results of a Delphi study.

INTRODUCTION: Standard treatment of newly diagnosed, advanced ovarian carcinoma (OC) consists of cytoreductive surgery followed by platinum-based chemotherapy with or without bevacizumab. Maintenance therapy with PARP inhibitors and olaparib-bevacizumab has recently shown to significantly improve progression-free survival in the first-line setting. Some practical aspects of maintenance therapy, however, are still poorly defined. AIM OF THE STUDY: To provide guidance to clinicians in the selection of maintenance therapy for newly diagnosed, advanced ovarian carcinoma. METHODS: A board of six gynecologic oncologists with expertise in the treatment of OC in Italy convened to address issues related to the new options for maintenance treatment. Based on scientific evidences, the board produced practice-oriented statements. Consensus was reached via a modified Delphi study that involved a panel of 22 experts from across Italy. RESULTS: Twenty-seven evidence- and consensus-based statements are presented, covering the following areas of interest: use of biomarkers (BRCA mutations and presence of homologous recombination deficiency); timing and outcomes of surgery; selection of patients eligible for bevacizumab; definition of response to treatment; toxicity and contraindications; evidence of synergy of bevacizumab plus PARP inhibitor. Two treatment algorithms are also included, for selecting maintenance therapy based on timing and outcomes of surgery, response to platinum-based chemotherapy and biomarker status. A score for the assessment of response to chemotherapy is proposed, but its validation is ongoing. CONCLUSIONS: We provide here consensus statements and treatment algorithms to guide clinicians in the selection of appropriate and personalized maintenance therapy in the first-line setting of advanced OC management.

Redistribution of CD8+ T cell subsets in metastatic renal cell carcinoma patients treated with anti-PD-1 therapy.

Renal-cell carcinoma (RCC) is responsible for the majority of tumors arising from the kidney parenchyma. Although a progressive improvement in median overall survival has been observed after the introduction of anti-PD-1 therapy, many patients do not benefit from this treatment. Therefore, we have investigated T cell dynamics to find immune modification induced by anti-PD-1 therapy. Here, we show that, after therapy, RCC patients (5 responders and 14 nonresponders) are characterized by a redistribution of different subsets across the memory T cell compartment.

Clinical Outcomes of Patients with Advanced Cancer and Pre-Existing Autoimmune Diseases Treated with Anti-Programmed Death-1 Immunotherapy: A Real-World Transverse Study.

BACKGROUND: Patients with a history of autoimmune diseases (AIDs) have not usually been included in clinical trials with immune checkpoint inhibitors. MATERIALS AND METHODS: Consecutive patients with advanced cancer, treated with anti-programmed death-1 (PD-1) agents, were evaluated according to the presence of pre-existing AIDs. The incidence of immune-related adverse events (irAEs) and clinical outcomes were compared among subgroups. RESULTS: A total of 751 patients were enrolled; median age was 69 years. Primary tumors were as follows: non-small cell lung cancer, 492 (65.5%); melanoma, 159 (21.2%); kidney cancer, 94 (12.5%); and others, 6 (0.8%). Male/female ratio was 499/252. Eighty-five patients (11.3%) had pre-existing AIDs, further differentiated in clinically active (17.6%) and inactive (82.4%). Among patients with pre-existing AIDs, incidence of irAEs of any grade was significantly higher when compared with patients without AIDs (65.9% vs. 39.9%). At multivariate analysis, both inactive (p = .0005) and active pre-existing AIDs (p = .0162), female sex (p = .0004), and Eastern Cooperative Oncology Group Performance Status <2 (p = .0030) were significantly related to a higher incidence of irAEs of any grade. No significant differences were observed regarding grade 3/4 irAEs and objective response rate among subgroups. Pre-existing AIDs were not significantly related with progression-free survival and overall survival. CONCLUSION: This study quantifies the increased risk of developing irAEs in patients with pre-existing AIDs who had to be treated with anti-PD-1 immunotherapy. Nevertheless, the incidence of grade 3/4 irAEs is not significantly higher when compared with control population. The finding of a greater incidence of irAEs among female patients ranks among the "hot topics" in gender-related differences in immuno-oncology. IMPLICATIONS FOR PRACTICE: Patients with a history of autoimmune diseases (AIDs) have not usually been included in clinical trials with immune checkpoint inhibitors but are frequent in clinical practice. This study quantifies the increased risk of developing immune-related adverse events (irAEs) in patients with pre-existing AIDs who had to be treated with anti-programmed death-1 immunotherapy. Nevertheless, their toxicities are mild and the incidence of grade 3/4 irAEs is not significantly higher compared with those of controls. These results will help clinicians in everyday practice, improving their ability to offer a proper counselling to patients, in order to offer an immunotherapy treatment even to patients with pre-existing autoimmune disease.

Safety and efficacy of nivolumab for metastatic renal cell carcinoma: real-world results from an expanded access programme.

OBJECTIVE: To report the safety and efficacy results of patients enrolled in the Italian Nivolumab Renal Cell Cancer Expanded Access Programme. PATIENTS AND METHODS: Patients with metastatic renal cell cancer (mRCC) previously treated with agents targeting the vascular endothelial growth factor pathway were eligible to receive nivolumab 3 mg/kg once every 2 weeks. Patients included in the analysis had received ≥1 dose of nivolumab and were monitored for adverse events (AEs) using Common Terminology Criteria for Adverse Events (CTCAE) v.4.0. RESULTS: A total of 389 patients were enrolled between July 2015 and April 2016, of whom 18% were aged ≥75 years, 6.7% had non-clear cell RCC, 49.6% had bone and 8.2% brain metastases, and 79% had received ≥2 previous lines of therapy. The most common any-grade treatment-related AEs were fatigue (13%) and rash (9%). Twenty-two patients (5.7%) discontinued treatment because of AEs. There were no treatment-related deaths. The objective response rate was 23.1%. At a median follow-up of 12 months, the median progression-free survival was 4.5 months (95% confidence interval 3.7-6.2) and the 12-month overall survival rate was 63%. Similar survival rates were reported among patients with non-clear-cell histology, elderly patients, those with bone and/or brain metastases, and those who had received prior first-line sunitinib or pazopanib, or prior everolimus. CONCLUSION: The safety and efficacy observed were consistent with those reported in the pivotal Checkmate 025 trial. Results in patients with non-clear-cell mRCC who were elderly, pretreated with everolimus, and had bone and/or brain metastases encourage the use of nivolumab in these categories of patients.

The outcome to axitinib or everolimus after sunitinib in metastatic renal cell carcinoma.

We aimed to investigate the different outcomes in patients with metastatic renal cell carcinoma treated with second-line axitinib or everolimus after sunitinib. Patients treated in 16 oncological centres in Italy were included, and those receiving axitinib or everolimus from January 2013 onwards were analysed for outcomes. Descriptive statistical tests were used to highlight differences between groups. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Data on 634 patients with metastatic renal cell carcinoma treated with first-line sunitinib have been obtained. A total of 182 patients received a second-line therapy with everolimus (79 patients, 43%) or axitinib (103 patients, 57%), respectively. The median PFS was 4.6 [95% confidence (CI): 2.6-6.5] months for patients treated with everolimus and 5.5 (95% CI: 4.3-6.7) months for patients treated with axitinib (P=0.7). The median OS was 13.9 (95% CI: 10.4-17.4) months for patients treated with everolimus and 12.0 (95% CI: 7.9-16.2) months for patients treated with axitinib (P=0.3). No differences were found based on length of first-line treatment. Major limitations are the retrospective nature of the study and the lack of a prospective evaluation of the progression. This study reports no significantly differences between everolimus and axitinib in terms of both PFS and OS. Furthermore, the length of first-line treatment cannot be used as such a predictive factor and cannot suggest the use of a molecule compared with another.

Enzalutamide after chemotherapy in advanced castration-resistant prostate cancer: the Italian Named Patient Program.

AIM: To collect efficacy and safety data of enzalutamide after docetaxel, we retrospectively evaluated the Italian Named Patient Program results. PATIENTS & METHODS: Two hundred and nine metastatic castration-resistant prostate cancer patients were enrolled. Median age was 73 years. Total 42.1% patients had pain, 14.4% had a performance status of two and 59.8% had a Gleason score ≥8. Total 31.1% had previously received ≥2 chemotherapies, 15.3 and 12% had been previously treated with abiraterone and cabazitaxel, respectively and 14.8% had received both. RESULTS:  Median progression-free survival and overall survival were 4.8 and 13.1 months, respectively. A prostate-specific antigen reduction ≥50% was observed in 49.1%. Total 32.7% abiraterone-pretreated patients achieved a biochemical response compared with 56% of abiraterone-naive patients. CONCLUSION:  Enzalutamide was safe and well tolerated. Its antitumor activity in abiraterone-pretreated patients was limited.

Outcome of Patients with Renal Cell Carcinoma and Multiple Glandular Metastases Treated with Targeted Agents.

PURPOSE: Pancreatic metastases (PM) from renal cell carcinoma (RCC) have been associated with long-term survival. The aim of this study was to evaluate the outcome of RCC patients with multiple glandular metastases (MGM) treated with targeted therapies (TTs). METHODS: Sixty-four MGM patients treated between 1993 and 2014 were retrospectively identified from a database of 274 RCC patients with PM from 11 European centers. The survival of MGM patients was compared with that of both patients with PM only and a cohort of 325 RCC patients with non-GM (control group) treated with TTs. Survival was estimated using the Kaplan-Meier method and was statistically compared using the log-rank test. RESULTS: Fifty-six patients (88%) had at least 2 MGM, 7 patients (11%) had 3 MGM and 1 patient had 4 MGM, while non-GM were present in the remaining patients. The median overall survival (OS) was 54.2 months for MGM and 73.4 months for patients with PM only. The median OS in the control group was 22.7 months and statistically inferior to both MGM (p < 0.001) and PM patients (p < 0.001). CONCLUSION: MGM from RCC are associated with a remarkable survival. Despite some limitations, these findings suggest that GM might be considered a predictor of a favorable prognosis.

Prognostic factors in patients receiving third line targeted therapy for metastatic renal cell carcinoma.

PURPOSE: Several prognostic models have been proposed for metastatic renal cell carcinoma but none has been validated in patients who receive third line targeted agents. We evaluated prognostic factors in patients with metastatic renal cell carcinoma who received a third line targeted agent. MATERIALS AND METHODS: We retrospectively reviewed data on 2,065 patients with clear cell metastatic renal cell carcinoma who were treated with targeted therapy at a total of 23 centers in Italy. Included in final analysis were 281 patients treated with 3 targeted agents. Overall survival was the main outcome. Cox proportional hazards regression followed by bootstrap validation was used to identify independent prognostic factors. RESULTS: Three clinical characteristics (ECOG performance status greater than 1, metastasis at diagnosis and liver metastasis) and 2 biochemical factors (hemoglobin less than the lower limit of normal and neutrophil count greater than the upper limit of normal, respectively) were prognostic. Patients were classified into 3 risk categories, including low-zero or 1, intermediate-2 and high risk-more than 2 risk factors. Median overall survival was 19.7, 10.1 and 5.5 months, and 1-year overall survival was 71%, 43% and 15%, respectively. The major limitation was the retrospective nature of this study and absent external validation. CONCLUSIONS: This nomogram included clinical and biochemical prognostic factors. In clinical trials it may be useful to select patients and define the prognosis.

Retrospective analysis on safety and efficacy of everolimus in treatment of metastatic renal cancer patients receiving dialysis.

AIMS: This retrospective study aimed to investigate safety and efficacy of everolimus in patients with metastatic renal cell carcinoma (mRCC) and end-stage renal disease requiring dialysis. PATIENTS & METHODS: From November 2009 to December 2012, 11 mRCC patients undergoing dialysis were treated with everolimus after failure of anti-VEGF therapy at six Italian institutions. Patient characteristics, safety and outcomes were collected. RESULTS: Progression-free survival and overall survival were determined using the Kaplan-Meier method. Median progression-free survival and overall survival were 9.01 and 15.7 months, respectively. No unexpected adverse events were reported. CONCLUSION: Everolimus appears to be safe in mRCC patients with renal impairment or end-stage renal disease requiring dialysis. Larger prospective studies are required to confirm these findings.

Sorafenib as first- or second-line therapy in patients with metastatic renal cell carcinoma in a community setting.

AIM: The Italian Retrospective Analysis of Sorafenib as First or Second Target Therapy study assessed the efficacy and safety of sorafenib in metastatic renal cell carcinoma patients treated in the community. PATIENTS & METHODS: Patients receiving first- or second-line single-agent sorafenib between January 2008 and December 2010 were eligible. Retrospective data collection started in 2012 and covers at least 1-year follow-up. The primary end point was overall survival (OS). RESULTS: Median OS was 17.2 months (95% CI: 15.5-19.6): 19.9 months (95% CI: 15.9-25.3) in patients treated with first-line sorafenib and 16.3 months (95% CI: 13.1-18.2) with second-line sorafenib. Overall median (95% CI) progression-free survival was 5.9 months (95% CI: 4.9-6.7): 6.6 (95% CI: 4.9-9.3) and 5.3 months (95% CI: 4.3-6.0) in first- and second-line patients, respectively. CONCLUSION: The efficacy and safety of sorafenib in routine community practice was generally good, especially in relation to OS in patients treated in the second line, where results were similar to those seen in recent prospective clinical trials.

Impact of the COVID-19 Pandemic on Prostate Cancer Diagnosis, Staging, and Treatment: A Population-Based Study in Northern Italy.

The COVID-19 pandemic has caused delays in cancer diagnoses and reductions in treatments. The aim of this work is to evaluate the impact of the pandemic on prostate cancer by evaluating whether there has been a shift towards more aggressive (Gleason) and more advanced tumors (stage IV) and a decline in treatments. The study was conducted on 1123 cases of prostate cancer incident in the Province of Reggio Emilia, Northern Italy, in the period of 2018-2021. In 2020, there was a decline in new diagnoses of prostate cancer (-31%), followed by a slight recovery in 2021 (+5%). While Gleason 7 and 8-10 values remained constant, a significant decrease was recorded in stage I (38.7%, 41.6%, 35.5%, and 27.7%) and an increase in stage IV (13.1%, 13%, 15.4%, and 20%) cases in the years 2018, 2019, 2020, and 2021, respectively. However, there was no impact on surgical treatment (which remained constant at around 35%) and radiotherapy (around 39%). Our findings underline the profound impact of COVID-19 on prostate cancer management, highlighting the importance of healthcare resilience in the face of unprecedented disruptions.

Molecular characterization as new driver in prognostic signatures and therapeutic strategies for endometrial cancer.

Endometrial cancer (EC) incidence and mortality rates have been increasing, particularly among young females. Although more than 90% of ECs are sporadic, 5-10% are hereditary, a majority of which occurs within Hereditary Non-Polyposis Colorectal Cancer syndrome (HNPCC) or Lynch syndrome. The traditional histopathological classification differentiates EC between two main groups: type I (or endometrioid) and type II (including all other histopathological subtypes). However, this classification lacks reproducibility and does not account for the emerging molecular heterogeneity. In 2013, The Cancer Genome Atlas (TCGA) project proposed EC molecular classification defining four groups with different prognostic and predictive values and the current international guidelines are progressively establishing EC risk stratification and treatment based on both histopathological and molecular criteria. Our manuscript aims to summarize the current state of EC molecular characterizations, including germline alterations at the basis of hereditary EC predisposition, to discuss their clinical utility as prognostic and predictive markers.

Pembrolizumab in Vaginal Carcinoma: A Case Report and Review of the Literature.

Introduction: Vaginal cancer is a rare gynecologic malignancy. While in a localized disease, concurrent chemoradiation grants local control and better overall survival, in a metastatic setting, the management options are very limited. Furthermore, recurrent cervical, vulvar, and vaginal carcinomas notoriously develop resistance to treatment, and consequently, their prognosis is still poor. Case Presentation: We herein present the case of a woman with a nodal relapse of vaginal carcinoma, effectively treated with third-line immunotherapy. We will also provide a review of the literature on the new therapeutic strategies for advanced vaginal carcinoma, with a focus on pembrolizumab immunotherapy. Conclusion: Pembrolizumab might represent a promising option for the management of vaginal and vulvar cancer, but data to support its use in this setting are still lacking. This case highlights the need for further investigation and trial designs for this rare disease.

Metastatic renal cell carcinoma: how to make the best sequencing decision after withdrawal for intolerance to a tyrosine kinase inhibitor.

With seven agents approved for metastatic renal cell carcinoma (RCC) within the past few years, there has undoubtedly been progress in treating this disease. The treatment safety of these new agents, however, now represents a crucial concern, which requires a search for the best possible balance between the minimization of the treatment burden and the need for maintaining appropriate drug dosages able to induce the best clinical benefit. In this review we have analyzed safety data of all approved targeted agents for metastatic RCC available as first- or second-line therapy to provide suggestions aimed at establishing the most appropriate second-line or later treatment on the basis of toxicities that have arisen in therapy. Based on the characteristics and comorbidities of the patients and on the toxicity profile of each treatment, it is possible to plan different therapeutic options. We, therefore, have compiled a list of points that are important to keep in mind when considering the use of the targeted drugs for the treatment of advanced RCC.

De Novo Metastatic Prostate Cancer: Are We Moving toward a Personalized Treatment?

De novo metastatic hormone-sensitive PC (mHSPC) accounts for 5-10% of all prostate cancer (PC) diagnoses but it is responsible for nearly 50% of PC-related deaths. Since 2015, the prognosis of mHSPC has slightly improved thanks to the introduction of new hormonal agents and chemotherapy combined with androgen deprivation therapy from the first-line setting. This review describes the current therapeutic opportunities for de novo mHSPC, focusing on potential molecular biomarkers identified in the main clinical trials that have modified the standard of care, the genomic features of de novo mHSPC, and the principal ongoing trials that are investigating new therapeutic approaches and the efficacy of a biomarker-guided treatment in this setting. The road toward personalized treatment for de novo mHSPC is still long, considering that the randomized clinical trials, which have furnished the basis of the current therapeutic options, stratified patients according to clinical criteria that did not necessarily reflect the biological rationale of the chosen therapy. The role of transcriptomic profiling of mHSPC as a predictive biomarker requires further validation, and it remains to be ascertained how the genomic variants detected in mHSPC, which are regarded as predictive in the castration-resistant disease, can be exploited in the mHSPC setting.

Immunotherapy in urothelial cancer: current status and future directions.

INTRODUCTION: Since 2016, the progressive use of immune checkpoint inhibitors (ICIs) starting from second-line treatment has led to an improvement in overall survival in locally advanced and metastatic urothelial cancer (UC). Clinical trials are underway testing the role of ICIs since the first stages of the disease, alone or in combination with standard therapies. AREAS COVERED: This review summarizes the current updated evidence regarding the role of ICIs in the different stages of UC, the ongoing clinical trials exploring the potential benefit of immunotherapy alone or in combination with standard-of-care therapies, as well as the promising association of ICIs with antibody-drug conjugates (ADCs). EXPERT OPINION: In the first-line setting, ICIs alone in platinum-unfit patients have shown unconvincing results; the ongoing EV-302 trial will probably suggest enfortumab vedotin plus pembrolizumab as a new effective option. The optimal duration of maintenance immunotherapy is still to be determined, finding a balance with the risk-benefit profile. The clinical benefit of ICIs as second-line treatment is limited to a subset of patients that cannot be definitively established yet. In the next 5 years, a lot of new ADCs will likely emerge for the treatment of UC.

nmCRPC, a look in the continuous care of prostate cancer patients: state of art and future perspectives.

Non-metastatic castration resistant prostate cancer (nmCRPC) is a clinical setting defined as confirmed rising levels of PSA in patients treated with ADT but without detectable metastases on conventional imaging with computerized tomography (CT) and technetium-99 m scintigraphy. Men with nmCRPC and a PSA doubling time (PSADT) ≤ 10 months are considered at high risk of rapidly developing metastases with a consequent possible impact on survival. Three recent phase III trials have demonstrated, in this setting, the efficacy of adding a next-generation androgen receptor targeted agent (ARTA) to ADT in respect to ADT only, in delaying the development of metastases (metastasis-free survival, MFS) and prolong overall survival. The magnitude of clinical benefit of these agents was even more meaningful if considering the low incidence of drug related adverse events. Our review described the latest advances in the management of nmCRPC, deriving from the pivotal clinical trials, SPARTAN, PROSPER and ARAMIS, in order to support clinicians to optimally manage these patients. Of note, the emergence of novel, more accurate, next-generation imaging techniques (including Ga PSMA-PET/CT), as well as eventual future tumor biomarkers, is modifying the entity and definition of the nmCRPC setting, with a consequent impact on patient's diagnosis and management.

Corrigendum: Optimizing the use of lenvatinib in combination with pembrolizumab in patients with advanced endometrial carcinoma.

[This corrects the article DOI: 10.3389/fonc.2022.979519.].