Background: Both novel hormonal therapies and docetaxel are approved for treatment of metastatic prostate cancer (mPC; in castration sensitive or refractory settings). Present knowledge gaps include ...lack of real-world data on treatment patterns in patients with newly diagnosed mPC, and comparative effectiveness of novel hormonal therapies (NHT) versus docetaxel after treatment with a prior NHT. Methods: Herein we extracted patient-level data from a large real-world database of patients with mPC in United States. Utilization of NHT or docetaxel for mPC and comparative effectiveness of an alternate NHT versus docetaxel after one prior NHT was evaluated. Comparative effectiveness was examined via Cox proportional hazards model with propensity score matching weights. Each patient’s propensity for treatment was modeled via random forest based on 22 factors potentially driving treatment selection. Results: The majority of patients (54%) received only androgen deprivation therapy for mPC. In patients treated with an NHT, alternate NHT was the most common next therapy and was associated with improved median overall survival over docetaxel (abiraterone followed by docetaxel vs. enzalutamide (8.7 vs. 15.6 months; adjusted hazards ratio; aHR 1.32; p = 0.009; and enzalutamide followed by docetaxel vs. abiraterone (9.7 vs. 13.2 months aHR 1.40; p = 0.009). Limitations of the study include retrospective design.
•Potential ways to maximize receipt of systemic therapies and overcome high attrition rate in patients with metastatic urothelial carcinoma: -.•Preventing or delaying metastatic disease by maximizing ...the receipt of neoadjuvant cisplatin-based therapy when the performance status is better than that in metastatic setting, and development of more effective and tolerated neoadjuvant and/or adjuvant therapies.•Aggressively advocating for the use of switch maintenance avelumab after response or stable disease with 4–6 cycles of platinum-based chemotherapy.•Developing effective and well-tolerated systemic therapies and assess those in earlier lines in the metastatic setting.•Development of novel biomarkers and imaging to personalize therapies.•Improving affordability and accessibility to systemic therapy agents and achieving equitable care.
Metastatic bladder cancer has poor overall survival. Though systemic therapies have shown to improve overall survival, real-world studies have shown that more than half of the patients do not receive any systemic therapy, while only around 15–20% receive second-line therapy. Even in patients receiving systemic therapies a disproportionately higher use of carboplatin is observed in the first line despite proven superior effectiveness of cisplatin. Reasons for these observations include moderate effectiveness and relatively toxicity of platinum-based chemotherapy regimens, concerns with performance status and co-morbidities in this predominantly older patient population, communications barriers, lack of social support, and access to affordable healthcare. Herein we discuss potential ways to overcome these challenges which include (1) preventing/delaying metastatic disease by maximizing the receipt of neoadjuvant cisplatin-based therapy, and development of better tolerated and more effective neoadjuvant and adjuvant therapies, (2) use of avelumab maintenance therapy after 4–6 cycles of platinum-based chemotherapy to overcome attrition of patients from first to second-line therapy, (3) advancing effective and well-tolerated systemic therapies such as enfortumab vedotin, and erdafitinib to the first-line metastatic setting or even to the localized setting, (4) further development of effective and well-tolerated therapies like sacituzumab govitecan, a novel antibody-drug conjugate and (5) improving affordability and accessibility to systemic therapy agents.
The treatment landscape of metastatic prostate cancer (mPCa) is rapidly evolving with the recent approvals of poly-ADP ribose polymerase inhibitors (PARPis) as monotherapy or as part of combination ...therapy with androgen receptor pathway inhibitors in patients with metastatic castration-resistant prostate cancer (mCRPC). Already part of the therapeutic armamentarium in different types of advanced cancers, these molecules have shaped a new era in mPCa by targeting genomic pathways altered in these patients, leading to promising responses. These agents act by inhibiting poly-ADP ribose polymerase (PARP) enzymes involved in repairing single-strand breaks in the DNA. Based on the PROfound and TRITON3 trials, olaparib and rucaparib were respectively approved as monotherapy in pretreated patients with mCRPC and alterations in prespecified genes. The combinations of olaparib with abiraterone (PROpel) and niraparib with abiraterone (MAGNITUDE) were approved as first-line options in patients with mCRPC and alterations in
, whereas the combination of talazoparib with enzalutamide (TALAPRO-2) was approved in the same setting in patients with alterations in any of the HRR genes, which are found in around a quarter of patients with advanced prostate cancer. Additional trials are already underway to assess these agents in an earlier hormone-sensitive setting. Future directions will include refining the treatment sequencing in patients with mCRPC in the clinic while taking into account the financial toxicity as well as the potential side effects encountered with these therapies and elucidating their mechanism of action in patients with non-altered HRR genes. Herein, we review the biological rationale behind using PARPis in mCRPC and the key aforementioned clinical trials that paved the way for these approvals.
•Three novel hormonal therapies, abiraterone, apalutamide, and enzalutamide, have been approved in metastatic castrate sensitive prostate cancer.•Docetaxel is recommended for patients with metastatic ...castrate sensitive prostate cancer while the benefit may be less certain in low-volume patients.•Relugolix, is the first oral, gonadotropin-releasing hormone antagonist to be approved for patients with advanced prostate cancer.•In future, somatic or germline alterations will potentially guide the management of metastatic castration sensitive prostate cancer.
Prostate cancer affects one in nine men and once metastatic is incurable. The treatment for metastatic castration-sensitive prostate cancer (mCSPC) has evolved rapidly over the last decade with the addition of upfront intensification with novel hormonal therapies (abiraterone, enzalutamide, apalutamide) or docetaxel in addition to androgen deprivation therapy. In this review, we discuss the phase III studies that lead to the approval of these upfront intensification therapies. We also review the recent approval of relugolix, the first oral, gonadotropin-releasing hormone antagonist for patients with advanced prostate cancer. A comparison of various agents is made and variables that can help in treatment selection are reviewed. We also summarize our current understanding of the role of germline and somatic alterations in the mCSPC setting. Finally, we review the ongoing clinical trials which can change the current treatment paradigm.
Type 1 diabetes mellitus (T1DM) is a rare, but serious immune-related adverse event (irAE) of immune checkpoint inhibitors (ICIs). Our goal was to characterize treatment outcomes associated with ...ICI-induced T1DM through analysis of clinical, immunological and proteomic data.
This was a single-center case series of patients with solid tumors who received ICIs and subsequently had a new diagnosis of T1DM. ICD codes and C-peptide levels were used to identify patients for chart review to confirm ICI-induced T1DM. Baseline blood specimens were studied for proteomic and immunophenotypic changes.
Between 2011 and 2023, 18 of 3744 patients treated at Huntsman Cancer Institute with ICIs were confirmed to have ICI-induced T1DM (0.48%). Eleven of the 18 patients received anti-PD1 monotherapy, 4 received anti-PD1 plus chemotherapy or targeted therapy, and 3 received ipilimumab plus nivolumab. The mean time to onset was 218 days (range 22-418 days). Patients had sudden elevated serum glucose within 2-3 weeks prior to diagnosis. Sixteen (89%) presented with diabetic ketoacidosis. Three of 12 patients had positive T1DM-associated autoantibodies. All patients with T1DM became insulin-dependent through follow-up. At median follow-up of 21.9 months (range 8.4-82.4), no patients in the melanoma group had progressed or died from disease. In the melanoma group, best responses were 2 complete response and 2 partial response while on active treatment; none in the adjuvant group had disease recurrence. Proteomic analysis of baseline blood suggested low inflammatory (IL-6, OSMR) markers and high metabolic (GLO1, DXCR) markers in ICI-induced T1DM cohort.
Our case series demonstrates rapid onset and irreversibility of ICI-induced T1DM. Melanoma patients with ICI-induced T1DM display excellent clinical response and survival. Limited proteomic data also suggested a unique proteomic profile. Our study helps clinicians to understand the unique clinical presentation and long-term outcomes of this rare irAE for best clinical management.
A 25-year-old male was admitted to the neurological intensive care unit for neurologic deterioration, likely caused by a paraneoplastic syndrome secondary to testicular malignancy. He experienced ...spontaneous rupture and hemorrhage of his testicular mass arising from an undescended testis while admitted. The tumor was excised, revealing a mixed germ cell tumor. Serum tumor markers began to rise after 4 cycles of chemotherapy. Surveillance scans 32 weeks after mass rupture revealed numerous tumor deposits throughout his peritoneum concerning for teratoma. We review a case of intraperitoneal metastasis of a testicular mixed germ cell tumor following intra-abdominal mass rupture.
Compared to the urban population, patients in rural areas face healthcare disparities and experience inferior healthcare-related outcomes. To compare the healthcare quality metrics and outcomes ...between patients with advanced genitourinary cancers from rural versus urban areas treated at a tertiary cancer hospital, in this retrospective study, eligible patients with advanced genitourinary cancers were treated at Huntsman Cancer Institute, an NCI-Designated Comprehensive Cancer Center in Utah. Rural–urban commuting area codes were used to classify the patients’ residences as being in urban (1–3) or rural (4–10) areas. The straight line distances of the patients’ residences from the cancer center were also calculated and included in the analysis. The median household income data were obtained and calculated from “The Michigan Population Studies Center”, based on individual zip codes. In this study, 2312 patients were screened, and 1025 eligible patients were included for further analysis (metastatic prostate cancer (n = 679), metastatic bladder cancer (n = 184), and metastatic renal cell carcinoma (n = 162). Most patients (83.9%) came from urban areas, while the remainder were from rural areas. Both groups had comparable demographic profiles and tumor characteristics at baseline. The annual median household income of urban patients was $8604 higher than that of rural patients (p < 0.001). There were fewer urban patients with Medicare (44.9% vs. 50.9%) and more urban patients with private insurance (40.4% vs. 35.1%). There was no difference between the urban and rural patients regarding receiving systemic therapies, enrollment in clinical trials, or tumor genomic profiling. The overall survival rate was not significantly different between the two populations in metastatic prostate, bladder, and kidney cancer, respectively. As available in a tertiary cancer hospital, access to care can mitigate the difference in the quality of healthcare and clinical outcomes in urban versus rural patients.
Metastatic urinary tract cancer (mUTC) is challenging to treat in older adults due to comorbidities. We compared the clinical courses of younger and older (≥70 years) adults with mUTC receiving ...first-line (1L) systemic therapy in a tertiary cancer center. Baseline clinical characteristics, treatments received, tolerability, and survival outcomes were analyzed. Among 212 patients (103 older vs. 109 younger), the older patients had lower hemoglobin at baseline (84% vs. 71%, p = 0.03), the majority were cisplatin-ineligible (74% vs. 45%, p < 0.001), received more immunotherapy-based treatments in the 1L (52% vs. 36%, p = 0.01), received fewer subsequent lines of treatment (median 0 vs. 1, p = 0.003), and had lower clinical trial participation (30% vs. 18%, p = 0.05) compared to the younger patients. When treated with 1L chemotherapy, older patients required more dose adjustments (53.4% vs. 23%, p = 0.001) and received fewer cycles of chemotherapy (median 4 vs. 5, p= 0.01). Older patients had similar OS (11.2 months vs. 14 months, p = 0.06) and similar rates of treatment-related severe toxicity and healthcare visits, independent of the type of systemic treatment received, compared to younger patients. We conclude that select older adults with mUTC can be safely treated with immunotherapy and risk-adjusted regimens of chemotherapy with tangible survival benefits.
An example of a combination regimen that met the primary endpoint in a registration trial in mCRPC was the combination of AKT and androgen receptor signalling inhibition using ipatasertib plus ...abiraterone in the IPATential150 trial.7 In IPATential150, the combination therapy significantly decreased the risk of radiographic progression (the coprimary endpoint) versus placebo plus abiraterone in men whose tumours were PTEN-deficient by immunohistochemistry, but not in unselected patients.7 Similarly, the improvement in secondary endpoints of median time to prostate-specific antigen (PSA) progression, PSA response, and confirmed objective response rate with the combination of ipatasertib plus abiraterone was more pronounced in men with PTEN-deficient tumours than in other patients. Overall survival data were not mature at the time of the report.7 Third, it is important to select patients who are at the highest risk of disease progression or death, and the most likely to benefit from synergistic combination therapies. The pembrolizumab plus olaparib regimen is being tested in patients with mCRPC on the basis of encouraging preclinical observation showing upregulation of tumour PD-L1 expression following treatment with PARP inhibitors.2 Treatment with cabozantinib (a multi-tyrosine kinase inhibitor) plus atezolizumab in patients with mCRPC previously treated with novel androgen receptor signalling inhibitors resulted in an unprecedented 80% disease control rate.2,6 These results led to an ongoing phase 3 trial (CONTACT-2; NCT04446117) of this novel immunotherapy-based combination, which is actively recruiting worldwide.
Cancers with mutations in BRCA2 have defective DNA repair capacity which is potentially targetable with poly-ADP(ribose) polymera se (PARP) inhibitors such as olaparib and rucaparib. However, the ...development of a secondary mutation that restores BRCA2 function is a well-documented mechanism of resistance to PARP inhibitors. Here, we present a case report of a man with metastatic castration-resistant prostate cancer with a germline BRCA2 frameshift mutation. Treatment with olaparib resulted in an initial response but was followed by progression. Cell-free DNA testing after progression revealed the presence of polyclonal BRCA2 mutations that were estimated to restore it into the correct reading frame. We describe his treatment course and genetic testing results and then discuss the biological mechanisms driving this mechanism of resistance.
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