Nivolumab plus rucaparib for metastatic castration-resistant prostate cancer: results from the phase 2 CheckMate 9KD trial.

BACKGROUND: CheckMate 9KD (NCT03338790) is a non-randomized, multicohort, phase 2 trial of nivolumab plus other anticancer treatments for metastatic castration-resistant prostate cancer (mCRPC). We report results from cohorts A1 and A2 of CheckMate 9KD, specifically evaluating nivolumab plus rucaparib. METHODS: CheckMate 9KD enrolled adult patients with histologically confirmed mCRPC, ongoing androgen deprivation therapy, and an Eastern Cooperative Oncology Group performance status of 0-1. Cohort A1 included patients with postchemotherapy mCRPC (1-2 prior taxane-based regimens) and ≤2 prior novel hormonal therapies (eg, abiraterone, enzalutamide, apalutamide); cohort A2 included patients with chemotherapy-naïve mCRPC and prior novel hormonal therapy. Patients received nivolumab 480 mg every 4 weeks plus rucaparib 600 mg two times per day (nivolumab dosing ≤2 years). Coprimary endpoints were objective response rate (ORR) per Prostate Cancer Clinical Trials Working Group 3 and prostate-specific antigen response rate (PSA50-RR; ≥50% PSA reduction) in all-treated patients and patients with homologous recombination deficiency (HRD)-positive tumors, determined before enrollment. Secondary endpoints included radiographic progression-free survival (rPFS), overall survival (OS), and safety. RESULTS: Outcomes (95% CI) among all-treated, HRD-positive, and BRCA1/2-positive populations for cohort A1 were confirmed ORR: 10.3% (3.9-21.2) (n=58), 17.2% (5.8-35.8) (n=29), and 33.3% (7.5-70.1) (n=9); confirmed PSA50-RR: 11.9% (5.9-20.8) (n=84), 18.2% (8.2-32.7) (n=44), and 41.7% (15.2-72.3) (n=12); median rPFS: 4.9 (3.7-5.7) (n=88), 5.8 (3.7-8.4) (n=45), and 5.6 (2.8-15.7) (n=12) months; and median OS: 13.9 (10.4-15.8) (n=88), 15.4 (11.4-18.2) (n=45), and 15.2 (3.0-not estimable) (n=12) months. For cohort A2 they were confirmed ORR: 15.4% (5.9-30.5) (n=39), 25.0% (8.7-49.1) (n=20), and 33.3% (7.5-70.1) (n=9); confirmed PSA50-RR: 27.3% (17.0-39.6) (n=66), 41.9 (24.5-60.9) (n=31), and 84.6% (54.6-98.1) (n=13); median rPFS: 8.1 (5.6-10.9) (n=71), 10.9 (6.7-12.0) (n=34), and 10.9 (5.6-12.0) (n=15) months; and median OS: 20.2 (14.1-22.8) (n=71), 22.7 (14.1-not estimable) (n=34), and 20.2 (11.1-not estimable) (n=15) months. In cohorts A1 and A2, respectively, the most common any-grade and grade 3-4 treatment-related adverse events (TRAEs) were nausea (40.9% and 40.8%) and anemia (20.5% and 14.1%). Discontinuation rates due to TRAEs were 27.3% and 23.9%, respectively. CONCLUSIONS: Nivolumab plus rucaparib is active in patients with HRD-positive postchemotherapy or chemotherapy-naïve mCRPC, particularly those harboring BRCA1/2 mutations. Safety was as expected, with no new signals identified. Whether the addition of nivolumab incrementally improves outcomes versus rucaparib alone cannot be determined from this trial. TRIAL REGISTRATION NUMBER: NCT03338790.

Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study.

BACKGROUND: Despite advances in the first-line treatment of metastatic renal cell carcinoma (RCC), there is an unmet need for options to address disease progression during or after treatment with immune checkpoint inhibitors (ICIs). Pembrolizumab and lenvatinib are active as monotherapies in RCC; thus, we aimed to evaluate the combination of lenvatinib plus pembrolizumab in these patients. METHODS: We report results of the metastatic RCC cohort from an open-label phase 1b/2 study of lenvatinib plus pembrolizumab in patients aged at least 18 years with selected solid tumours and an Eastern Cooperative Oncology Group performance status of 0-1. Oral lenvatinib at 20 mg was given once daily along with intravenous pembrolizumab at 200 mg once every 3 weeks. Patients remained on study drug treatment until disease progression, development of unacceptable toxicity, or withdrawal of consent. Efficacy was analysed in patients with clear cell metastatic RCC receiving study drug by previous therapy grouping: treatment naive, previously treated ICI naive (previously treated with at least one line of therapy but not with an anti-PD-1 or anti-PD-L1 ICI), and ICI pretreated (ie, anti-PD-1 or anti-PD-L1) patients. Safety was analysed in all enrolled and treated patients. The primary endpoint was the objective response rate at week 24 per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) by investigator assessment. This trial is registered with ClinicalTrials.gov (NCT02501096) and with the EU Clinical Trials Register (EudraCT2017-000300-26), and is closed to new participants. FINDINGS: Between July 21, 2015, and Oct 16, 2019, 145 patients were enrolled in the study. Two patients had non-clear cell RCC and were excluded from the efficacy analysis (one in the treatment-naive group and one in the ICI-pretreated group); thus, the population evaluated for efficacy comprised 143 patients (n=22 in the treatment-naive group, n=17 in the previously treated ICI-naive group, and n=104 in the ICI-pretreated group). All 145 enrolled patients were included in the safety analysis. The median follow-up was 19·8 months (IQR 14·3-28·4). The number of patients with an objective response at week 24 by irRECIST was 16 (72·7%, 95% CI 49·8-89·3) of 22 treatment-naive patients, seven (41·2%, 18·4-67·1) of 17 previously treated ICI-naive patients, and 58 (55·8%, 45·7-65·5) of 104 ICI-pretreated patients. Of 145 patients, 82 (57%) had grade 3 treatment-related adverse events and ten (7%) had grade 4 treatment-related adverse events. The most common grade 3 treatment-related adverse event was hypertension (30 [21%] of 145 patients). Treatment-related serious adverse events occurred in 36 (25%) patients, and there were three treatment-related deaths (upper gastrointestinal haemorrhage, sudden death, and pneumonia). INTERPRETATION: Lenvatinib plus pembrolizumab showed encouraging antitumour activity and a manageable safety profile and might be an option for post-ICI treatment of metastatic RCC. FUNDING: Eisai and Merck Sharp & Dohme.

Safety and Clinical Activity of Atezolizumab in Patients with Metastatic Castration-Resistant Prostate Cancer: A Phase I Study.

PURPOSE: Atezolizumab [anti-programmed death-ligand 1 (anti-PD-L1)] is well tolerated and efficacious in multiple cancers, but has not been previously evaluated in metastatic castration-resistant prostate cancer (mCRPC). This study examined the safety, efficacy, and biomarkers of atezolizumab monotherapy for mCRPC. PATIENTS AND METHODS: This phase Ia, open-label, dose-escalation and dose-expansion study (PCD4989g) enrolled patients with mCRPC who had progressed on sipuleucel-T or enzalutamide. Atezolizumab was given intravenously every 3 weeks until confirmed disease progression or loss of clinical benefit. Prespecified endpoints included safety, efficacy, biomarker analyses, and radiographic assessments. RESULTS: All 35 evaluable patients [median age, 68 years (range, 45-83 years)] received atezolizumab after ≥1 prior line of therapy; 62.9% of patients had received ≥3 prior lines. Treatment-related adverse events occurred in 21 patients (60.0%), with no deaths. One patient had a confirmed partial response (PR) per RECIST 1.1, and 1 patient had a PR per immune-related response criteria. The confirmed 50% PSA response rate was 8.6% (3 patients). Median overall survival (OS) was 14.7 months [95% confidence interval (CI): 5.9-not evaluable], with a 1-year OS rate of 52.3% (95% CI: 34-70); 2-year OS was 35.9% (95% CI: 13-59). Median follow-up was 13.0 months (range, 1.2-28.1 months). Biomarker analyses showed that atezolizumab activated immune responses; however, a composite biomarker failed to reveal consistent correlations with efficacy. CONCLUSIONS: Atezolizumab was generally well tolerated in patients with mCRPC, with a safety profile consistent with other tumor types. In heavily pretreated patients, atezolizumab monotherapy demonstrated evidence of disease control; however, its limited efficacy suggests a combination approach may be needed.

Cisplatin Therapy Does Not Worsen Renal Function in Severe Antenatal Bartter Syndrome.

A 30-year-old man with severe antenatal Bartter syndrome, diagnosed and treated in infancy, developed testicular carcinoma. Despite the known renal complications of cisplatin, this drug was used for his chemotherapy because of its superior antineoplastic effect. Nonsteroidal anti-inflammatory drug administration was continued during cisplatin therapy. Despite an increase in his oral potassium requirement, renal function was maintained following completion of chemotherapy. In spite of its significant associated nephrotoxicity, cisplatin can be used in patients with severe antenatal Bartter syndrome if required for therapy of malignancy.

Telemedicine-Enabled Clinical Trial of Metformin in Patients With Prostate Cancer.

PURPOSE: Clinical trials are critical to informing cancer care but often are hampered by slow accrual and lack of generalizability because of poor geographic accessibility. We tested the feasibility of replacing onsite study visits with telemedicine visits in a prospective clinical trial. METHODS: Castration-naïve patients with prostate cancer and a rising serum prostate-specific antigen after definitive local therapy were eligible. Patients were required to have a single onsite visit for enrollment. Study treatment consisted of oral metformin 850 mg daily for 1 month followed by 850 mg twice daily for 5 months. Telehealth video visits (televisits) were conducted monthly by using a Health Insurance Portability and Accountability Act-compliant smartphone application. The primary objective was to determine the feasibility of telemedicine-enabled study visits. Secondary objectives were defining safety, anticancer activity, quality of life, and patient satisfaction. RESULTS: Fifteen patients with a median age of 68 years (range, 57 to 83 years) and median one-way driving time to the study center of 71 minutes (range, 12 to 147 minutes) were enrolled. The patients completed 84 eligible televisits (completion rate, 100%; 95% CI, 0.80 to 1). Diarrhea was the most common adverse event but was limited to grade 1 in severity; a single patient experienced grade ≥ 3 adverse events. Seven patients (46.7%; 95% CI, 24.8% to 69.9%) had a ≤ 20% increase in prostate-specific antigen relative to baseline. Patients agreed or strongly agreed that they would participate in a telemedicine-enabled clinical trial in the future. CONCLUSION: To our knowledge, this interventional oncology clinical trial is the first to be conducted through telemedicine. Telemedicine-enabled trials are feasible and may overcome geographic barriers to trial participation. Metformin was generally well tolerated but associated with modest anticancer activity.

Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial.

BACKGROUND: First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients. METHODS: For this single-arm, multicentre, phase 2 study, in 47 academic medical centres and community oncology practices in seven countries in North America and Europe, we recruited previously untreated patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible. Patients were given 1200 mg intravenous atezolizumab every 21 days until progression. The primary endpoint was independently confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (central review), assessed in prespecified subgroups based on PD-L1 expression and in all patients. All participants who received one or more doses of atezolizumab were included in the primary and safety analyses. This study was registered with ClinicalTrials.gov, number NCT02108652. FINDINGS: Between June 9, 2014, and March 30, 2015, we enrolled 123 patients, of whom 119 received one or more doses of atezolizumab. At 17·2 months' median follow-up, the objective response rate was 23% (95% CI 16 to 31), the complete response rate was 9% (n=11), and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2·7 months (2·1 to 4·2). Median overall survival was 15·9 months (10·4 to not estimable). Tumour mutation load was associated with response. Treatment-related adverse events that occurred in 10% or more of patients were fatigue (36 [30%] patients), diarrhoea (14 [12%] patients), and pruritus (13 [11%] patients). One treatment-related death (sepsis) occurred. Nine (8%) patients had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12%) patients. INTERPRETATION: Atezolizumab showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use in untreated metastatic urothelial cancer. FUNDING: F Hoffmann-La Roche, Genentech.

Everolimus combined with gefitinib in patients with metastatic castration-resistant prostate cancer: Phase 1/2 results and signaling pathway implications.

BACKGROUND: The effects of mammalian target of rapamycin (mTOR) inhibition are limited by feedback reactivation of receptor tyrosine kinase signaling in phosphatase and tensin homolog-null tumors. Thus, this study tested the combination of mTOR inhibition (everolimus) and epidermal growth factor receptor inhibition (gefitinib) in castration-resistant prostate cancer (CRPC). METHODS: In phase 1, 12 patients (10 with CRPC and 2 with glioblastoma) received daily gefitinib (250 mg) with weekly everolimus (30, 50, or 70 mg). In phase 2, 27 CRPC patients received gefitinib with everolimus (70 mg). RESULTS: Phase 1 revealed no pharmacokinetic interactions and no dose-limiting toxicities. In phase 2, 18 of 27 patients (67%) discontinued treatment before the 12-week evaluation because of progression as evidenced by prostate-specific antigen (PSA) levels (n = 6) or imaging (n = 5) or because of a grade 2 or higher toxicity (n = 7). Thirteen of the 37 CRPC patients (35%) exhibited a rapidly rising PSA level after they had begun treatment, and this declined upon discontinuation. Fluorodeoxyglucose positron emission tomography 24 to 72 hours after the initiation of treatment showed a decrease in the standardized uptake value consistent with mTOR inhibition in 27 of the 33 evaluable patients (82%); there was a corresponding rise in PSA in 20 of these 27 patients (74%). CONCLUSIONS: The combination of gefitinib and everolimus did not result in significant antitumor activity. The induction of PSA in tumors treated with mTOR inhibitors was consistent with preclinical data showing that phosphoinositide 3-kinase (PI3K) pathway signaling feedback inhibits the androgen receptor (AR). This clinical evidence of relief of feedback inhibition promoting enhanced AR activity supports future studies combining PI3K pathway inhibitors and second-generation AR inhibitors in CRPC.

Zbtb7a suppresses prostate cancer through repression of a Sox9-dependent pathway for cellular senescence bypass and tumor invasion.

Zbtb7a has previously been described as a powerful proto-oncogene. Here we unexpectedly demonstrate that Zbtb7a has a critical oncosuppressive role in the prostate. Prostate-specific inactivation of Zbtb7a leads to a marked acceleration of Pten loss-driven prostate tumorigenesis through bypass of Pten loss-induced cellular senescence (PICS). We show that ZBTB7A physically interacts with SOX9 and functionally antagonizes its transcriptional activity on key target genes such as MIA, which is involved in tumor cell invasion, and H19, a long noncoding RNA precursor for an RB-targeting microRNA. Inactivation of Zbtb7a in vivo leads to Rb downregulation, PICS bypass and invasive prostate cancer. Notably, we found that ZBTB7A is genetically lost, as well as downregulated at both the mRNA and protein levels, in a subset of human advanced prostate cancers. Thus, we identify ZBTB7A as a context-dependent cancer gene that can act as an oncogene in some contexts but also has oncosuppressive-like activity in PTEN-null tumors.

Models of self and others and their relation to positive and negative caregiving responses.

The burden of providing informal care to a family member can lead to caregiver depression and potentially harmful caregiving behavior. Given the interpersonal nature of caregiving, the relationship between caregivers and care recipients may impact caregiver responses. We applied attachment theory to understanding caregiver depression, and both potentially harmful and exemplary caregiving responses. We present data from 430 caregivers in the Family Relationships in Late Life (FRILL 2) Project, a multisite, longitudinal study of caregiving. Age, gender, and model of self were related to caregiving responses, suggesting that model of self may help identify caregivers at risk for poor responses.

Endorsement of proactively aggressive caregiving strategies moderates the relation between caregiver mental health and potentially harmful caregiving behavior.

This research tested the proposition that the oft-reported relation between caregiver mental health outcomes (i.e., resentment, depression) and potentially harmful caregiver behavior (PHB) would be mediated or moderated by caregiver endorsement of proactively aggressive caregiving strategies (PA). Caregiver resentment was the strongest predictor of PHB in the sample of 417 informal caregivers who resided with their care recipients; in fact, resentment mediated the impact of caregiver depression, thus suggesting that depressed affect was associated with PHB only if depressed caregivers resented their caregiving burdens. As predicted, caregiver endorsement of PA moderated the relation between resentment and PHB, such that links between these two constructs were strongest when caregivers were high in both resentment and PA. Endorsement of PA also mediated the relations between demographic or contextual variables (i.e., income, care recipient dementia) and PHB. Implications of these results for research and intervention are discussed.

Circulating tumor cell analysis in patients with progressive castration-resistant prostate cancer.

PURPOSE: To better direct targeted therapies to the patients with tumors that express the target, there is an urgent need for blood-based assays that provide expression information on a consistent basis in real time with minimal patient discomfort. We aimed to use immunomagnetic-capture technology to isolate and analyze circulating tumor cells (CTC) from small volumes of peripheral blood of patients with advanced prostate cancer. EXPERIMENTAL DESIGN: Blood was collected from 63 patients with metastatic prostate cancer. CTCs were isolated by the Cell Search system, which uses antibodies to epithelial cell adhesion marker and immunomagnetic capture. CTCs were defined as nucleated cells positive for cytokeratins and negative for CD45. Captured cells were analyzed by immunofluorescence, Papanicolau staining, and fluorescence in situ hybridization. RESULTS: Most patients (65%) had 5 or more CTCs per 7.5 mL blood sample. Cell counts were consistent between laboratories (c = 0.99) and did not change significantly over 72 or 96 h of storage before processing (c = 0.99). Their identity as prostate cancer cells was confirmed by conventional cytologic analysis. Molecular profiling, including analysis of epidermal growth factor receptor (EGFR) expression, chromosome ploidy, and androgen receptor (AR) gene amplification, was possible for all prostate cancer patients with >or=5 CTCs. CONCLUSIONS: The analysis of cancer-related alterations at the DNA and protein level from CTCs is feasible in a hospital-based clinical laboratory. The alterations observed in EGFR and AR suggest that the methodology may have a role in clinical decision making.

Differential exoprotease activities confer tumor-specific serum peptidome patterns.

Recent studies have established distinctive serum polypeptide patterns through mass spectrometry (MS) that reportedly correlate with clinically relevant outcomes. Wider acceptance of these signatures as valid biomarkers for disease may follow sequence characterization of the components and elucidation of the mechanisms by which they are generated. Using a highly optimized peptide extraction and matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF) MS-based approach, we now show that a limited subset of serum peptides (a signature) provides accurate class discrimination between patients with 3 types of solid tumors and controls without cancer. Targeted sequence identification of 61 signature peptides revealed that they fall into several tight clusters and that most are generated by exopeptidase activities that confer cancer type-specific differences superimposed on the proteolytic events of the ex vivo coagulation and complement degradation pathways. This small but robust set of marker peptides then enabled highly accurate class prediction for an external validation set of prostate cancer samples. In sum, this study provides a direct link between peptide marker profiles of disease and differential protease activity, and the patterns we describe may have clinical utility as surrogate markers for detection and classification of cancer. Our findings also have important implications for future peptide biomarker discovery efforts.

Critical function for ADAM9 in mouse prostate cancer.

ADAM9 is a membrane-anchored metalloprotease that is markedly up-regulated in several human carcinomas. Here, we show that ADAM9 is similarly up-regulated in mouse models for prostate, breast, and intestinal carcinoma. To assess whether ADAM9 is critical for the pathogenesis of prostate carcinoma, one of the most common cancers in men, we evaluated how loss of ADAM9 affects tumorigenesis in W(10) mice, a mouse model for this disease. In the absence of ADAM9, most tumors in 50-week-old W(10) mice were well differentiated, whereas littermate controls expressing wild-type ADAM9 had predominantly poorly differentiated, and in some cases significantly larger, tumors. Moreover, gain-of-function experiments in which ADAM9 was overexpressed in mouse prostate epithelium resulted in significant abnormalities, including epithelial hyperplasia at 4 to 6 months of age, and prostatic intraepithelial neoplasia after 1 year. A potential underlying mechanism for the role of ADAM9 in prostate cancer emerged from cell-based assays: ADAM9 can cleave and release epidermal growth factor and FGFR2iiib from cells, both of which have pivotal functions in the pathogenesis of this disease. Taken together, these results suggest that ADAM9 contributes to the pathogenesis of prostate cancer and potentially also other carcinomas, raising the possibility that ADAM9 might be a good target for antitumor drugs.

Evidence for a p27 tumor suppressive function independent of its role regulating cell proliferation in the prostate.

Reduced p27 levels correlate with poor prognosis in a wide spectrum of human tumors and can accelerate tumorigenesis in mouse tissues. To determine whether p27 deficiency can accelerate tumorigenesis in tissues with inactive Rb and p53 pathways, we examined the effect of p27 status on prostate tumorigenesis in mice expressing simian virus 40 large T antigen (LT). In p27-deficient mice expressing LT, tumors progressed from high-grade prostatic intraepithelial neoplasia to poorly differentiated carcinoma at a greatly accelerated rate. p27 deficiency could not collaborate with a mutant of LT that fails to inactivate the Rb pathway alone. Furthermore, p27 deficiency does not increase the proliferation index, reduce the apoptotic index, or affect the expression of E2F-dependent genes in cells expressing LT at any stage of the disease. Expression of LT alone leads to maximal proliferation, but p27 deficiency still increases the amount of cyclin A and cyclin-dependent kinase 2-associated kinase activity in tissues. Interestingly, this model recapitulates an important feature of the human disease, specifically a high frequency of allelic loss of chromosome 16q, which is syntenic to mouse chromosome 8. Loss of heterozygosity may accelerate the inactivation of other tumor suppressors, such as E-cadherin, which are located in this interval. These experiments provide direct physiological and causal evidence that p27 has tumor suppressive functions independent of its role regulating cell proliferation.

Prostate cancer: a dynamic illness with shifting targets.

Despite high response rates and palliative clinical benefits, androgen ablation does not cure advanced prostate cancer because of the inevitable emergence of resistant cells. Many new therapies under development for prostate cancer target pathways and molecules that contribute to the growth and survival of these cells. The rational and effective use of targeted therapies to eradicate resistant populations of tumour cells should be grounded on the premise that prostate cancer is a dynamic disease that evolves as it progresses, and that specific molecular determinants mediating sensitivity and resistance may be relevant only during specific states of the disease. Directed approaches must account for this changing dynamic so that clinical outcomes may be improved.

Caregiver models of self and others, coping, and depression: predictors of depression in children with chronic pain.

In a sample of 59 chronically ill pediatric patients and their maternal caregivers, both child-reported pain and caregiver-reported depression predicted child-reported depression. Results further suggested that the association between pain and depression in children is ameliorated by caregiver coping strategies and that how caregivers cope is a function of their attachment-related representations of the self and others. Caregivers with a negative model of the self were more depressed. and those with a negative model of others were more prone to use avoidant coping strategies, and, in turn, to be more depressed. However, the extent to which caregivers with negative models of self used more avoidant and less approach coping appeared to depend on whether they perceived that others were likely to respond to their needs.