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BACKGROUND: PARP (poly(ADP-ribose) polymerase) inhibitors (PARPi) are now standard of care in metastatic castrate-resistant prostate cancer (mCRPC) patients with select mutations in DNA damage repair (DDR) pathways, but patients with ATM- and BRCA2 mutations may respond differently to PARPi. We hypothesized that differences may also exist in response to taxanes, which may inform treatment sequencing decisions. METHODS: mCRPC patients (N = 158) with deleterious ATM or BRCA2 mutations who received taxanes, PARPi, or both were retrospectively identified from 11 US academic centers. Demographic, treatment, and survival data were collected. Kaplan-Meier analyses were performed and Cox hazard ratios (HR) were calculated for progression-free survival (PFS) as well as overall survival (OS), from time of first taxane or PARPi therapy. RESULTS: Fifty-eight patients with ATM mutations and 100 with BRCA2 mutations were identified. Fourty-four (76%) patients with ATM mutations received taxane only or taxane before PARPi, while 14 (24%) received PARPi only or PARPi before taxane. Patients with ATM mutations had longer PFS when taxane was given first versus PARPi given first (HR: 0.74 [95% confidence interval [CI]: 0.37-1.50]; p = 0.40). Similarly, OS was longer in patients with ATM mutations who received taxane first (HR: 0.56 [CI: 0.20-1.54]; p = 0.26). Among patients with BRCA2 mutations, 51 (51%) received taxane first and 49 (49%) received PARPi first. In contrast, patients with BRCA2 mutations had longer PFS when PARPi was given first versus taxane given first (HR: 0.85 [CI: 0.54-1.35]; p = 0.49). Similarly, OS was longer in patients with BRCA2 mutations who received PARPi first (HR: 0.75 [CI: 0.41-1.37]; p = 0.35). CONCLUSIONS: Our retrospective data suggest differential response between ATM and BRCA2 mutated prostate cancers in terms of response to PARPi and to taxane chemotherapy. When considering the sequence of PARPi versus taxane chemotherapy for mCRPC with DDR mutations, ATM, and BRCA2 mutation status may be helpful in guiding choice of initial therapy.
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Inibidores de Poli(ADP-Ribose) Polimerases , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Estudos Retrospectivos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Resultado do Tratamento , Taxoides/uso terapêutico , Proteína BRCA2/genética , Proteínas Mutadas de Ataxia Telangiectasia/genéticaRESUMO
BACKGROUND: To date, single-agent immune checkpoint inhibitor (CPI) therapy has proven to be ineffective against biomarker-unselected extrapulmonary poorly differentiated neuroendocrine carcinomas (EP-PDNECs). The efficacy of CPI in combination with chemotherapy remains under investigation. METHODS: Patients with advanced, progressive EP-PDNECs were enrolled in a two-part study of pembrolizumab-based therapy. In Part A, patients received pembrolizumab alone. In Part B, patients received pembrolizumab plus chemotherapy. PRIMARY ENDPOINT: objective response rate (ORR). Secondary endpoints: safety, progression-free survival (PFS) and overall survival (OS). Tumours were profiled for programmed death-ligand 1 expression, microsatellite-high/mismatch repair deficient status, mutational burden (TMB), genomic correlates. Tumour growth rate was evaluated. RESULTS: Part A (N = 14): ORR (pembrolizumab alone) 7% (95% CI, 0.2-33.9%), median PFS 1.8 months (95% CI, 1.7-21.4), median OS 7.8 months (95% CI, 3.1-not reached); 14% of patients (N = 2) had grade 3/4 treatment-related adverse events (TRAEs). Part B (N = 22): ORR (pembrolizumab plus chemotherapy) 5% (95% CI, 0-22.8%), median PFS 2.0 months (95% CI, 1.9-3.4), median OS 4.8 months (95% CI, 4.1-8.2); 45% of patients (N = 10) had grade 3/4 TRAEs. The two patients with objective response had high-TMB tumours. DISCUSSION: Treatment with pembrolizumab alone and pembrolizumab plus chemotherapy was ineffective in advanced, progressive EP-PDNECs. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03136055.
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Carcinoma Neuroendócrino , Tumores Neuroendócrinos , Humanos , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/genética , Tumores Neuroendócrinos/tratamento farmacológico , Intervalo Livre de ProgressãoRESUMO
BACKGROUND: DNA damage repair mutations (DDRm) are common in patients with metastatic castration-resistant prostate cancer (mCRPC). The optimal standard therapy for this population is not well described. METHODS: A multi-institutional, retrospective study of patients with mCRPC and DDRm was conducted. Patient data, including systemic therapies and responses, were collected. The decline in prostate-specific antigen ≥ 50% from baseline (PSA50) and overall survival (OS) from the treatment start were compared by mutation and treatment type. A multivariable Cox proportional hazards model for OS was created that controlled for DDRm, first-line treatment received for mCRPC, and clinical factors. RESULTS: The most common DDRm observed among 149 men with mCRPC were BRCA1/2 (44%), CDK12 (32%), and ATM (15%). The majority received first-line abiraterone (40%) or enzalutamide (30%). The PSA50 rate with first-line abiraterone was lower for CDK12 (52%) than BRCA1/2 (89%; P = .02). After first-line abiraterone or enzalutamide, the median OS was longest with second-line carboplatin-chemotherapy (38 months) in comparison with abiraterone or enzalutamide (33 months), docetaxel (17 months), or cabazitaxel (11 months; P = .02). PSA50 responses to carboplatin-based chemotherapy were higher for BRCA1/2 (79%) than ATM (14%; P = .02) or CDK12 (38%; P = .08). In a multivariable analysis, neither the specific DDRm type nor the first-line treatment was associated with improved OS. CONCLUSIONS: Responses to standard therapies were generally superior in patients with BRCA1/2 mutations and inferior in patients with ATM or CDK12 mutations. The DDRm type did not independently predict OS. After progression on first-line abiraterone or enzalutamide, carboplatin-based chemotherapy was associated with the longest OS. These findings may inform treatment discussions and clinical trial design and require prospective validation.
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Neoplasias de Próstata Resistentes à Castração , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteína BRCA1/genética , Carboplatina/uso terapêutico , Quinases Ciclina-Dependentes/genética , Docetaxel/uso terapêutico , Humanos , Masculino , Nitrilas/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Treatment options for advanced thyroid cancer refractory to standard therapies are limited. The safety and efficacy of pembrolizumab were evaluated in patients with advanced differentiated thyroid cancer expressing programmed death ligand 1 (PD-L1). METHODS: Patients with advanced thyroid cancer were enrolled in the nonrandomized, phase Ib KEYNOTE-028 trial conducted to evaluate safety and antitumor activity of the anti-programmed death 1 (PD-1) antibody pembrolizumab in advanced solid tumors. Key eligibility criteria were advanced papillary or follicular thyroid cancer, failure of standard therapy, and PD-L1 expression in tumor or stroma cells (assessed by immunohistochemistry). Pembrolizumab 10 mg/kg was administered every 2 weeks up to 24 months or until confirmed progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: Twenty-two patients were enrolled: median age was 61 years; 59% were women; and 68% had papillary carcinoma. Median follow-up was 31 months (range, 7-34 months). Treatment-related adverse events were observed in 18 (82%) patients; those occurring in ≥15% of patients were diarrhea (n = 7) and fatigue (n = 4). One grade ≥ 3 treatment-related adverse event occurred (colitis, grade 3); no treatment-related discontinuations or deaths occurred. Two patients had confirmed partial response, for an ORR of 9% (95% confidence interval [CI], 1-29%); response duration was 8 and 20 months. Median progression-free survival was 7 months (95% CI, 2-14 months); median overall survival was not reached (95% CI, 22 months to not reached). CONCLUSIONS: Results of this phase Ib proof-of-concept study suggest that pembrolizumab has a manageable safety profile and demonstrate evidence of antitumor activity in advanced differentiated thyroid cancer in a minority of patients treated. Further analyses are necessary to confirm these findings. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02054806 . Registered 4 February 2014.
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Adenocarcinoma Folicular/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Câncer Papilífero da Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Adenocarcinoma Folicular/metabolismo , Adulto , Idoso , Antígeno B7-H1/metabolismo , Colite/induzido quimicamente , Diarreia/induzido quimicamente , Fadiga/induzido quimicamente , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudo de Prova de Conceito , Critérios de Avaliação de Resposta em Tumores Sólidos , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Resultado do Tratamento , Adulto JovemRESUMO
The treatment of advanced prostate cancer has changed significantly in the last decade, as a result of the introduction of multiple new systemic therapies that have had a positive impact on treatment outcomes. The increasing number of therapies, along with new insights into the biological underpinnings of prostate cancer, have led to a growing appreciation for the heterogeneity of the disease and an awareness of emerging subcategories that have direct therapeutic implications for the practicing clinician. In the metastatic hormone-naive setting, the extent of metastatic disease visible on scans can serve as a useful measure to guide treatment decisions; the addition of docetaxel chemotherapy to hormonal therapy has significant benefit in patients whose scans show more extensive disease. In the castration-resistant setting, abiraterone and enzalutamide have both had a transformative impact; however, the emergence of resistance to these therapies often heralds a more aggressive phenotype. Emerging clinically relevant subcategories include disease that demonstrates treatment-emergent neuroendocrine differentiation, as well as tumors with somatic and/or germline alterations in the DNA repair pathway. Identification of these subtypes has direct clinical relevance with regard to the potential benefit of platinum-based chemotherapy, poly (ADP-ribose) polymerase inhibitors, and likely further therapies as new therapeutic targets are identified in these groups.
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Antineoplásicos Hormonais/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias de Próstata Resistentes à Castração , Ensaios Clínicos como Assunto , Humanos , Masculino , Estadiamento de Neoplasias , Prognóstico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/terapia , Resultado do TratamentoRESUMO
177Lu can be imaged after administration using SPECT/CT. Most work to date has focused on using posttreatment imaging to measure normal organ and tumor dose. We aimed to assess the impact of posttreatment SPECT/CT on the management of patients undergoing 177Lu-prostate-specific membrane antigen (PSMA) radiopharmaceutical therapy (RPT). Methods: In this retrospective study, 122 patients underwent PSMA RPT with subsequent SPECT/CT 24 h after treatment. We determined a qualitative response at each cycle and reviewed patient charts to assess the impact that posttreatment SPECT/CT had on patient management. Changes in patient management were classified as changes on the basis of progression and response, and specific cycles when they occurred were noted. Miscellaneous changes in patient management were also evaluated. Results: Among the 122 consecutive patients examined, 42%-56% exhibited stable disease, whereas 19%-39% of patients exhibited response on visual assessment across treatment cycles. In total, 49% (n = 60) of patients experienced changes in management, of which 57% (n = 34) were due to progression, 40% (n = 24) were due to response, and 3% (n = 2) were due to miscellaneous changes. Changes due to disease progression were observed mostly after cycles 2 and 4. Changes due to response to RPT occurred mostly after cycles 3 and 4. Conclusion: At our center, 49% of patients experienced changes in management based on posttreatment SPECT/CT, and most of these changes occurred at cycles 2 and 4. Integrating posttreatment SPECT/CT into routine PSMA RPT protocols can aid in patient management.
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Improved imaging modalities are needed to accurately stage patients with muscle-invasive bladder cancer (MIBC) and metastatic urothelial carcinoma. Imaging with small-molecule ligands or inhibitors of fibroblast activation protein (FAP) is a promising modality that has demonstrated initial efficacy across a broad range of tumors. We present our experience with the novel FAP-peptide binder 68Ga-FAP-2286 in patients with MIBC. Methods: Patients with histopathologically confirmed bladder cancer who had either localized disease at diagnosis (localized cohort, n = 13) or known metastatic disease (metastatic cohort, n = 8) were imaged with 68Ga-FAP-2286 PET as part of a clinical trial (NCT04621435). The SUVmax of 68Ga-FAP-2286 PET-positive lesions and lesion size were documented. In patients who had available 18F-FDG PET performed within 45 d of 68Ga-FAP-2286 PET (n = 5), uptake on the 2 scans was compared. When there was a discrepancy between imaging modalities on retrospective review, biopsy of suggestive lesions was performed as the standard of care. Results: In the metastatic and localized cohorts, 36 and 18 68Ga-FAP-2286-avid lesions, respectively, were identified across multiple anatomic locations, including lymph nodes, visceral metastases, and bones. Fourteen of 36 lesions in the metastatic cohort and 14 of 18 lesions in the localized cohort were lymph nodes measuring less than 1 cm. Among lesions measuring less than 0.5 cm, 0.5-1 cm, and more than 1 cm, average SUVmax was 5.2 ± 2.6, 9.6 ± 3.7, and 13.0 ± 4.3, respectively, in the metastatic cohort and 10.5 ± 5.1, 10.8 ± 5.7, and 9.9 ± 5.4, respectively, in the localized cohort. Five patients had 18F-FDG PET available for comparison. The average SUVmax for lesions avid on 68Ga-FAP-2286 PET and 18F-FDG PET was 9.9 ± 3.4 versus 4.2 ± 1.9, respectively (n = 16 lesions). For 3 patients in the localized cohort, 68Ga-FAP-2286 PET informed clinical management, including identification of both false-positive findings on 18F-FDG PET and false-negative findings on conventional CT. Conclusion: 68Ga-FAP-2286 imaging is highly sensitive in patients with urothelial cancer and is effective in identifying metastatic lesions across a variety of anatomic sites, including subcentimeter lymph nodes that would not have raised suspicion on conventional scans. This novel imaging modality may inform clinical decision-making in patients with MIBC both by refining local nodal staging and by defining metastatic disease that would otherwise be undetectable on conventional imaging.
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Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Humanos , Radioisótopos de Gálio , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Neoplasias da Bexiga Urinária/diagnóstico por imagem , Tomografia por Emissão de PósitronsRESUMO
Denosumab is a fully human mAb that binds receptor activator of NFκB ligand (RANKL). It is routinely administered to patients with cancer to reduce the incidence of new bone metastasis. RANK-RANKL interactions regulate bone turnover by controlling osteoclast recruitment, development, and activity. However, these interactions also can regulate immune cells including dendritic cells and medullary thymic epithelial cells. Inhibition of the latter results in reduced thymic negative selection of T cells and could enhance the generation of tumor-specific T cells. We examined whether administering denosumab could modify modulate circulating immune cells in patients with cancer. Blood was collected from 23 patients with prostate cancer and 3 patients with renal cell carcinoma, all of whom had advanced disease and were receiving denosumab, prior to and during denosumab treatment. Using high-dimensional mass cytometry, we found that denosumab treatment by itself induced modest effects on circulating immune cell frequency and activation. We also found minimal changes in the circulating T-cell repertoire and the frequency of new thymic emigrants with denosumab treatment. However, when we stratified patients by whether they were receiving chemotherapy and/or steroids, patients receiving these concomitant treatments showed significantly greater immune modulation, including an increase in the frequency of natural killer cells early and classical monocytes later. We also saw broad induction of CTLA-4 and TIM3 expression in circulating lymphocytes and some monocyte populations. These findings suggest that denosumab treatment by itself has modest immunomodulatory effects, but when combined with conventional cancer treatments, can lead to the induction of immunologic checkpoints. See related Spotlight by Nasrollahi and Davar, p. 383.
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Neoplasias Ósseas , Denosumab , Humanos , Masculino , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/prevenção & controle , Neoplasias Ósseas/secundário , Denosumab/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Ligante RANK/antagonistas & inibidores , Neoplasias da Próstata/tratamento farmacológicoRESUMO
We sought to evaluate the efficacy of WEE1 inhibitor adavosertib in patients with solid tumor malignancies (cohort A) and clear cell renal cell carcinoma (ccRCC; cohort B). NCT03284385 was a parallel cohort, Simon two-stage, phase II study of adavosertib (300 mg QDAY by mouth on days 1-5 and 8-12 of each 21-day cycle) in patients with solid tumor malignancies harboring a pathogenic SETD2 mutation. The primary endpoint was the objective response rate. Correlative assays evaluated the loss of H3K36me3 by IHC, a downstream consequence of SETD2 loss, in archival tumor tissue. Eighteen patients were enrolled (9/cohort). The median age was 60 years (range 45-74). The median duration of treatment was 1.28 months (range 0-24+). No objective responses were observed in either cohort; accrual was halted following stage 1. Minor tumor regressions were observed in 4/18 (22%) evaluable patients. Stable disease (SD) was the best overall response in 10/18 (56%) patients, including three patients with SD > 4 months. One patient with ccRCC remains on treatment for >24 months. The most common adverse events of any grade were nausea (59%), anemia (41%), diarrhea (41%), and neutropenia (41%). Nine patients (50%) experienced a Grade ≥3 adverse event. Of eight evaluable archival tissue samples, six (75%) had a loss of H3K36me3 by IHC. Adavosertib failed to exhibit objective responses in SETD2-altered ccRCC and other solid tumor malignancies although prolonged SD was observed in a subset of patients. Combination approaches may yield greater depth of tumor response. SIGNIFICANCE: WEE1 inhibition with adavosertib monotherapy demonstrated limited clinical activity in patients with SETD2-altered solid tumors despite compelling preclinical data indicating a synthetic lethal effect, which did not translate into robust tumor regression. Loss of the H3K36me3 trimethylation mark caused by SETD2-deficiency was confirmed in the majority of evaluable tumors. A subset of patients derived clinical benefit as manifested by minor tumor regressions and prolonged SD.
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Proteínas de Ciclo Celular , Histona-Lisina N-Metiltransferase , Proteínas Tirosina Quinases , Pirazóis , Humanos , Pessoa de Meia-Idade , Histona-Lisina N-Metiltransferase/genética , Masculino , Idoso , Feminino , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/antagonistas & inibidores , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/patologia , Pirimidinonas/uso terapêutico , Pirimidinonas/farmacologia , Pirimidinonas/administração & dosagem , MutaçãoRESUMO
Fibroblast activation protein (FAP), expressed in the tumor microenvironment of a variety of cancers, has become a target of novel PET tracers. The purpose of this report is to evaluate the imaging characteristics of 68Ga-FAP-2286, present the first-to our knowledge-dosimetry analysis to date, and compare the agent with 18F-FDG and FAPI compounds. Methods: Patients were administered 219 ± 43 MBq of 68Ga-FAP-2286 and scanned after 60 min. Uptake was measured in up to 5 lesions per patient and within the kidneys, spleen, liver, and mediastinum (blood pool). Absorbed doses were evaluated using MIM Encore and OLINDA/EXM version 1.1 using the International Commission on Radiological Protection publication 103 tissue weighting factor. Results: Forty-six patients were imaged with 68Ga-FAP-2286 PET. The highest average uptake was seen in sarcoma, cholangiocarcinoma, and colon cancer. The lowest uptake was found in lung cancer and testicular cancer. The average SUVmax was significantly higher on 68Ga-FAP-2286 PET than on 18F-FDG PET in cholangiocarcinoma (18.2 ± 6.4 vs. 9.1 ± 5.0, P = 0.007), breast cancer (11.1 ± 6.8 vs. 4.1 ± 2.2, P < 0.001), colon cancer (13.8 ± 2.2 vs. 7.6 ± 1.7, P = 0.001), hepatocellular carcinoma (9.3 ± 3.5 vs. 4.7 ± 1.3, P = 0.01), head and neck cancer (11.3 ± 3.5 vs. 7.6 ± 5.5, P = 0.04), and pancreatic adenocarcinoma (7.4 ± 1.8 vs. 3.7 ± 1.0, P = 0.01). The total-body effective dose was estimated at 1.16E-02 mSv/MBq, with the greatest absorbed organ dose in the urinary bladder wall (9.98E-02 mGy/MBq). Conclusion: 68Ga-FAP-2286 biodistribution, dosimetry, and tumor uptake were similar to those of previously reported FAPI compounds. Additionally,68Ga-FAP-2286 PET had consistently higher uptake than 18F-FDG PET. These results are especially promising in the setting of small-volume disease and differentiating tumor from inflammatory uptake.
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Fluordesoxiglucose F18 , Radioisótopos de Gálio , Neoplasias , Tomografia por Emissão de Pósitrons , Radiometria , Humanos , Fluordesoxiglucose F18/farmacocinética , Masculino , Feminino , Neoplasias/diagnóstico por imagem , Neoplasias/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Pessoa de Meia-Idade , Distribuição Tecidual , Idoso , Adulto , Compostos Radiofarmacêuticos/farmacocinética , Idoso de 80 Anos ou mais , QuinolinasRESUMO
BACKGROUND: Dickkopf-related protein 1 (DKK1) is a Wingless-related integrate site (Wnt) signaling modulator that is upregulated in prostate cancers (PCa) with low androgen receptor expression. DKN-01, an IgG4 that neutralizes DKK1, delays PCa growth in pre-clinical DKK1-expressing models. These data provided the rationale for a clinical trial testing DKN-01 in patients with metastatic castration-resistant PCa (mCRPC). METHODS: This was an investigator-initiated parallel-arm phase 1/2 clinical trial testing DKN-01 alone (monotherapy) or in combination with docetaxel 75 mg/m2 (combination) for men with mCRPC who progressed on ≥1 AR signaling inhibitors. DKK1 status was determined by RNA in-situ expression. The primary endpoint of the phase 1 dose escalation cohorts was the determination of the recommended phase 2 dose (RP2D). The primary endpoint of the phase 2 expansion cohorts was objective response rate by iRECIST criteria in patients treated with the combination. RESULTS: 18 pts were enrolled into the study-10 patients in the monotherapy cohorts and 8 patients in the combination cohorts. No DLTs were observed and DKN-01 600 mg was determined as the RP2D. A best overall response of stable disease occurred in two out of seven (29%) evaluable patients in the monotherapy cohort. In the combination cohort, five out of seven (71%) evaluable patients had a partial response (PR). A median rPFS of 5.7 months was observed in the combination cohort. In the combination cohort, the median tumoral DKK1 expression H-score was 0.75 and the rPFS observed was similar between patients with DKK1 H-score ≥1 versus H-score = 0. CONCLUSION: DKN-01 600 mg was well tolerated. DKK1 blockade has modest anti-tumor activity as a monotherapy for mCRPC. Anti-tumor activity was observed in the combination cohorts, but the response duration was limited. DKK1 expression in the majority of mCRPC is low and did not clearly correlate with anti-tumor activity of DKN-01 plus docetaxel.
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Androgen deprivation therapy (ADT) is associated with better outcomes for men with biochemical recurrence following treatment for localized prostate cancer but can predispose patients to a higher risk of cardiovascular events. Intermittent ADT is worth considering in this setting, with close monitoring of prostate-specific antigen to decide when to restart ADT after off-treatment periods.
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Doenças Cardiovasculares , Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/terapia , Antagonistas de Androgênios/efeitos adversos , Antineoplásicos Hormonais/uso terapêutico , Resultado do Tratamento , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controleRESUMO
PURPOSE: Germline testing for men with prostate cancer (PCa) poses numerous implementation barriers. Alternative models of care delivery are emerging, but implementation outcomes are understudied. We evaluated implementation outcomes of a hybrid oncologist- and genetic counselor-delivered model called the genetic testing station (GTS) created to streamline testing and increase access. METHODS: A prospective, single-institution, cohort study of men with PCa referred to the GTS from October 14, 2019, to October 14, 2021, was conducted. Using the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework, we described patients referred to GTS (Reach), the association of GTS with germline testing completion rates within 60 days of a new oncology appointment in a pre- versus post-GTS multivariable logistic regression (Effectiveness), Adoption, Implementation, and Maintenance. Because GTS transitioned from an on-site to remote service during the COVID-19 pandemic, we also compared outcomes for embedded versus remote GTS. RESULTS: Overall, 713 patients were referred to and eligible for GTS, and 592 (83%) patients completed germline testing. Seventy-six (13%) patients had ≥ 1 pathogenic variant. Post-GTS was independently associated with higher odds of completing testing within 60 days than pre-GTS (odds ratio, 8.97; 95% CI, 2.71 to 29.75; P < .001). Black race was independently associated with lower odds of testing completion compared with White race (odds ratio, 0.35; 95% CI, 0.13 to 0.96; P = .042). There was no difference in test completion rates or patient-reported decisional conflict for embedded versus remote GTS. GTS has been adopted by 31 oncology providers across four clinics, and implementation fidelity was high with low patient loss to follow-up, but staffing costs are a sustainability concern. CONCLUSION: GTS is a feasible, effective model for high-volume germline testing in men with PCa, both in person and using telehealth. GTS does not eliminate racial disparities in germline testing access.
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COVID-19 , Neoplasias da Próstata , Telemedicina , Masculino , Humanos , Estudos de Coortes , Pandemias , Estudos Prospectivos , Testes Genéticos , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genética , Células Germinativas/patologiaRESUMO
BACKGROUND: Radiopharmaceuticals, including Ga-68-prostate specific membrane antigen (PSMA)-11 and F-18-Fluciclovine, are increasingly used to inform therapies for prostate cancer (CaP). Stereotactic body radiation therapy (SBRT) to PET-detected oligometastatic CaP has been shown to improve progression free survival (PFS) and delay androgen deprivation therapy (ADT) compared to observation. For men who subsequently develop oligorecurrent CaP, outcomes following second SBRT are unknown. METHODS: A retrospective cohort study was conducted. Eligibility criteria included patients with oligometastatic (1-5 lesions) CaP detected on PSMA or Fluciclovine PET who underwent 2 consecutive SBRT courses to tracer-avid sites. Data on stage, tracer type, concurrent systemic therapy, and prostate-specific antigen (PSA) responses for first SBRT (SBRT1) and second SBRT (SBRT2) were collected. Outcomes included PSA decline ≥50% (PSA50), PFS after SBRT2, and ADT initiation or intensification-free survival after SBRT2. Factors potentially associated with PSA50 after SBRT2 was evaluated with multivariable logistic regression. Factors potentially associated with PFS and ADT initiation/intensification-free survival after SBRT2 were evaluated with separate multivariable Cox proportional-hazards models. RESULTS: Twenty-five patients were identified. At SBRT2, oligorecurrence was detected on PSMA and Fluciclovine PET in 17 (68%) and 8 (32%) patients, respectively. Fifteen (60%) patients had castration-sensitive disease and 10 (40%) had castration-resistant disease. After SBRT2, 16 (64%) achieved a PSA50 response, median PFS was 11.0mo, and median ADT initiation/intensification-free survival was 23.2mo. On multivariable analysis, maximum percent change in PSA after SBRT1 (OR 0.94, 95%CI 0.88-0.99, Pâ¯=â¯0.046) and concurrent change in systemic therapy (OR 21.61, 95%CI 1.12-417.9, Pâ¯=â¯0.042) were associated with PSA50 responses after SBRT2. PSA50 response after SBRT1 was associated with improved PFS (HR 0.36, 95%CI 0.00-0.42, Pâ¯=â¯0.008) and ADT initiation/intensification-free survival (HR 0.07, 95%CI 0.01-0.68, Pâ¯=â¯0.021) after SBRT2. From SBRT1 to last follow-up (median 48 months), 7 (28%) patients remained ADT-free. CONCLUSIONS: Serial SBRT for oligometastatic CaP detected on PSMA or Fluciclovine PET is feasible and can achieve PSA declines, with or without systemic therapy. Degree of biochemical response to first SBRT warrants further study as a potential predictor of PSA response, PFS, and ADT initiation/intensification-free survival following a subsequent SBRT course. This preliminary evidence provides rationale for larger, prospective studies of this strategy.
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Neoplasias da Próstata , Radiocirurgia , Masculino , Humanos , Neoplasias da Próstata/patologia , Antígeno Prostático Específico , Radioisótopos de Gálio , Resultado do Tratamento , Antagonistas de Androgênios , Estudos Retrospectivos , Estudos ProspectivosRESUMO
BACKGROUND: Skeletal-related events (SREs) from bone metastases disease carry significant morbidity in men with metastatic castration resistant prostate cancer (mCRPC). The differential risk of SREs among patients receiving abiraterone acetate (AA) or enzalutamide (ENZ) is unknown. METHODS: To compare the risk of SREs among men with mCRPC receiving AA or ENZ, a retrospective cohort study using the SEER-Medicare Linked Database was conducted. Men with prostate cancer aged ≥65 years at first AA or ENZ prescription (index date) from 2011 to 2015 were identified. Patients were followed until the earliest occurrence of SRE, death, Medicare disenrollment, or December 31, 2016. The primary outcome was a composite endpoint of SRE (pathologic fracture, spinal cord compression, or surgery or radiation to bone) after the index date. Multivariable logistic regressions including key demographic and clinical covariates with death as a competing risk were conducted. RESULTS: Overall, 5,856 patients were identified (4,207 received AA and 1,649 received ENZ). Median age was 76.5 years (IQR 71.4-82.3), 4,557 (77.8%) were White, 1,112 (19.2%) had recent chemotherapy, and 2,730 (46.6%) had recent zoledronic acid or denosumab. Eight-hundred and thirty-seven (14.3%) patients had ≥1 SRE after index date. In multivariable analyses, there was no difference in SRE risk based on AA and ENZ (HR=0.99 for ENZ, 95%CI 0.84-1.16, P=0.890). Denosumab was associated with lower SRE risk (HR=0.75, 95%CI 0.64-0.88, P=0.001). CONCLUSIONS: In this large cohort of men with mCRPC, there was no difference in risk of SRE between AA and ENZ. Decision-making should be informed by prior therapies, comorbidities, toxicity profiles, and patient preferences. Denosumab has evidence of benefit in preventing SREs in this real-world population.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Acetato de Abiraterona/uso terapêutico , Idoso , Androstenos , Benzamidas , Denosumab/efeitos adversos , Humanos , Masculino , Medicare , Nitrilas , Feniltioidantoína , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Estudos Retrospectivos , Resultado do Tratamento , Estados Unidos/epidemiologiaRESUMO
PURPOSE: Men with metastatic castration-resistant prostate cancer increasingly encounter complex treatment decisions. Consultation audio recordings and summaries promote patient informed decision making but are underutilized. Mobile recording software applications may increase access. Little is known regarding the feasibility of implementation in clinical encounters. METHODS: We conducted a mixed-methods pilot study in men with progressive metastatic castration-resistant prostate cancer. We instructed patients to use a mobile software application to record an oncology visit. Patients could share the recording with our patient scribing program to receive a written summary. We assessed feasibility and acceptability with postvisit surveys. We measured patient-reported helpfulness of the intervention in decision making and change in Decisional Conflict Scale-informed subscale. We conducted semistructured interviews to explore implementation and analyzed transcripts using thematic analysis. RESULTS: Across 20 patients, 18 (90%) recorded their visits. Thirteen of 18 (72%) listened to the recording, and 14 of 18 (78%) received a summary. Eighteen of 20 (90%) visits were telehealth. Fourteen patients (70% of all 20; 78% of 18 question respondents) found the application easy to use. Nine patients (50% of 18 recording patients; 90% of 10 question respondents) reported that the recording helped treatment decision making. Decisional conflict decreased from baseline to 1-week postvisit (47.4-28.5, P < .001). Interviews revealed benefits, facilitators, contextual factors, and technology and patient-related barriers to recordings and summaries. CONCLUSION: In this single-institution academic setting, a mobile application for patients to record consultations was a feasible, acceptable, and potentially valued intervention that improved decision making in the telehealth setting. Studies in larger, diverse populations are needed.
Assuntos
Tomada de Decisões , Neoplasias de Próstata Resistentes à Castração , Humanos , Masculino , Projetos Piloto , Encaminhamento e Consulta , TecnologiaRESUMO
The PI3K pathway may be a potential mechanism to overcome cisplatin resistance. We conducted a phase Ib trial of alpelisib and cisplatin for patients with solid tumor malignancies with planned dose expansion in HPV-associated tumors. The primary objective was to determine the MTD and recommended phase II dose. Two different weekly doses of cisplatin (30 and 35 mg/m2) were evaluated with escalating doses of alpelisib, administered daily during a 21-day treatment cycle. Twenty-three patients were enrolled: 91% received >3 prior regimens with median of 4 (range 1-10), and 78% progressed on prior platinum. The MTD was alpelisib 250 mg daily with weekly cisplatin 30 mg/m2. There were 3 DLTs: all grade 4 hyperglycemia. Frequent treatment-related adverse events of any grade included fatigue (52%), diarrhea (39%), nausea (38%), hyperglycemia (30%), anemia (22%), and nephropathy (17%). Hyperglycemia was linked to baseline hemoglobin A1C, but not body mass index. Twelve patients discontinued treatment for toxicity (n = 9 during cycle 1) and 11 discontinued for progression. Of 14 evaluable patients who received at least one treatment cycle, 4 (29%) patients demonstrated partial response, and 7 had stable disease for a disease control rate of 79%. The median PFS measured 4.3 months (95% CI, 1.6-4.5). No difference in PFS was observed between PIK3CA-mutated and wild-type tumors. While the combination of alpelisib and cisplatin demonstrated preliminary evidence of activity despite platinum resistance, toxicities hindered prolonged treatment. Prospective studies are planned using carboplatin and alpelisib to improve toxicity and tolerability. Significance: The PI3K inhibitor alpelisib has limited activity alone, but there is interest in combinations in platinum-resistant tumors. In this phase Ib study of alpelisib with cisplatin, the objective response rate measured 29% but adverse events limited dose intensity. These promising results provide rationale for studying combinations with better tolerated platinum agents.
Assuntos
Cisplatino , Neoplasias , Humanos , Cisplatino/efeitos adversos , Fosfatidilinositol 3-Quinases/metabolismo , Estudos Prospectivos , Neoplasias/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 QuinaseAssuntos
Antígenos de Neoplasias/metabolismo , Proteínas de Membrana/metabolismo , Imagem Molecular/métodos , Tomografia por Emissão de Pósitrons/métodos , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/metabolismo , Humanos , Masculino , Metástase Neoplásica , Cuidados Pré-Operatórios , Prostatectomia , Neoplasias da Próstata/terapia , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/terapia , Compostos Radiofarmacêuticos , Recidiva , Resultado do TratamentoRESUMO
PURPOSE: ZEN-3694 is a bromodomain extraterminal inhibitor (BETi) with activity in androgen-signaling inhibitor (ASI)-resistant models. The safety and efficacy of ZEN-3694 plus enzalutamide was evaluated in a phase Ib/IIa study in metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Patients had progressive mCRPC with prior resistance to abiraterone and/or enzalutamide. 3+3 dose escalation was followed by dose expansion in parallel cohorts (ZEN-3694 at 48 and 96 mg orally once daily, respectively). RESULTS: Seventy-five patients were enrolled (N = 26 and 14 in dose expansion at low- and high-dose ZEN-3694, respectively). Thirty (40.0%) patients were resistant to abiraterone, 34 (45.3%) to enzalutamide, and 11 (14.7%) to both. ZEN-3694 dosing ranged from 36 to 144 mg daily without reaching an MTD. Fourteen patients (18.7%) experienced grade ≥3 toxicities, including three patients with grade 3 thrombocytopenia (4%). An exposure-dependent decrease in whole-blood RNA expression of BETi targets was observed (up to fourfold mean difference at 4 hours post-ZEN-3694 dose; P ≤ 0.0001). The median radiographic progression-free survival (rPFS) was 9.0 months [95% confidence interval (CI), 4.6-12.9] and composite median radiographic or clinical progression-free survival (PFS) was 5.5 months (95% CI, 4.0-7.8). Median duration of treatment was 3.5 months (range, 0-34.7+). Lower androgen receptor (AR) transcriptional activity in baseline tumor biopsies was associated with longer rPFS (median rPFS 10.4 vs. 4.3 months). CONCLUSIONS: ZEN-3694 plus enzalutamide demonstrated acceptable tolerability and potential efficacy in patients with ASI-resistant mCRPC. Further prospective study is warranted including in mCRPC harboring low AR transcriptional activity.
Assuntos
Androstenos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Benzamidas/administração & dosagem , Nitrilas/administração & dosagem , Feniltioidantoína/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Androstenos/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas/efeitos adversos , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Nitrilas/efeitos adversos , Feniltioidantoína/efeitos adversos , Intervalo Livre de Progressão , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/genética , Resultado do TratamentoRESUMO
OBJECTIVES: The net oncogenic effect of ß2-adrenergic receptor ADRB2, whose downstream elements induce neuroendocrine differentiation and whose expression is regulated by EZH2, is unclear. ADRB2 expression and associated clinical outcomes in metastatic castration-resistant prostate cancer (mCRPC) are unknown. METHODS AND MATERIALS: This was a retrospective analysis of a multi-center, prospectively enrolled cohort of mCRPC patients. Metastatic biopsies were obtained at progression, and specimens underwent laser capture microdissection and RNA-seq. ADRB2 expression was stratified by histology and clustering based on unsupervised hierarchical transcriptome analysis and correlated with EZH2 expression; an external dataset was used for validation. The association between ADRB2 expression and overall survival (OS) was assessed by log-rank test and a multivariable Cox proportional hazard model. RESULTS: One hundred and twenty-seven patients with progressive mCRPC had sufficient metastatic tumor for RNA-seq. ADRB2 expression was lowest in the small cell-enriched transcriptional cluster (P < 0.01) and correlated inversely with EZH2 expression (râ¯=â¯-0.28, P < 0.01). These findings were validated in an external cohort enriched for neuroendocrine differentiation. Patients with tumors harboring low ADRB2 expression (lowest quartile) had a shorter median OS than those with higher (9.5 vs. 20.5 months, Pâ¯=â¯0.02). In multivariable analysis, low ADRB2 expression was associated with a trend toward shorter OS (HR for deathâ¯=â¯1.54, 95%CI 0.98-2.44). Conversely, higher expression of upstream transcriptional regulator EZH2 was associated with shortened OS (HR for deathâ¯=â¯3.01, 95%CI 1.12-8.09). CONCLUSIONS: Low ADRB2 expression is associated with neuroendocrine differentiation and is associated with shortened survival. EZH2 is a potential therapeutic target for preventing neuroendocrine transdifferentiation and improving outcomes in mCRPC. Further studies of agents targeting ß-adrenergic signaling are warranted.