Cabazitaxel: a novel second-line treatment for metastatic castration-resistant prostate cancer

Until recently, patients with castration-resistant prostate cancer (CRPC) had limited therapeutic options once they became refractory to docetaxel chemotherapy, and no treatments improved survival. This changed in June 2010 when the Food and Drug Administration (FDA) approved cabazitaxel as a new option for patients with CRPC whose disease progresses during or after docetaxel treatment. For most of these patients, cabazitaxel will now replace mitoxantrone (a drug that was FDA-approved because of its palliative effects) as the treatment of choice for docetaxel-refractory disease. The approval of cabazitaxel was based primarily on the TROPIC trial, a large (n = 755) randomized Phase III study showing an overall median survival benefit of 2.4 months for men with docetaxel-pretreated metastatic CRPC receiving cabazitaxel (with prednisone) compared to mitoxantrone (with prednisone). Cabazitaxel is a novel tubulin-binding taxane that differs from docetaxel because of its poor affinity for P-glycoprotein (P-gp), an ATP-dependent drug efflux pump. Cancer cells that express P-gp become resistant to taxanes, and the effectiveness of docetaxel can be limited by its high substrate affinity for P-gp. Preclinical and early clinical studies show that cabazitaxel retains activity in docetaxel-resistant tumors, and this was confirmed by the TROPIC study. Common adverse events with cabazitaxel include neutropenia (including febrile neutropenia) and diarrhea, while neuropathy was rarely observed. Thus, the combination of cabazitaxel and prednisone is an important new treatment option for men with docetaxel-refractory metastatic CRPC, but this agent should be administered cautiously and with appropriate monitoring (especially in men at high risk of neutropenic complications)

Prostate cancer: AR aberrations and resistance to abiraterone or enzalutamide

Resistance to abiraterone or enzalutamide is a major medical burden the duration of benefit is highly variable and cross-resistance often occurs when these two agents are given sequentially. Blood-based analysis of androgen receptor splice variants and AR copy number gain or mutations could enhance understanding of the mechanisms of resistance and improve management of patients with castration-resistant prostate cancer

Pan-cancer interrogation of MUTYH variants reveals biallelic inactivation and defective base excision repair across a spectrum of solid tumors

Purpose Biallelic germline pathogenic variants of the base excision repair (BER) pathway gene MUTYH predispose to colorectal cancer (CRC) and other cancers. The possible association of heterozygous variants with broader cancer susceptibility remains uncertain. This study investigated the prevalence and consequences of pathogenic MUTYH variants and MUTYH loss of heterozygosity (LOH) in a large pan-cancer analysis. Materials and Methods Data from 354,366 solid tumor biopsies that were sequenced as part of routine clinical care were analyzed using a validated algorithm to distinguish germline from somatic MUTYH variants. Results Biallelic germline pathogenic MUTYH variants were identified in 119 tissue biopsies. Most were CRCs and showed increased tumor mutational burden (TMB) and a mutational signature consistent with defective BER (COSMIC Signature SBS18). Germline heterozygous pathogenic variants were identified in 5,991 biopsies and their prevalence was modestly elevated in some cancer types. About 12% of these cancers (738 samples: including adrenal gland cancers, pancreatic islet cell tumors, nonglioma CNS tumors, GI stromal tumors, and thyroid cancers) showed somatic LOH for MUTYH, higher rates of chromosome 1p loss (where MUTYH is located), elevated genomic LOH, and higher COSMIC SBS18 signature scores, consistent with BER deficiency. Conclusion This analysis of MUTYH alterations in a large set of solid cancers suggests that in addition to the established role of biallelic pathogenic MUTYH variants in cancer predisposition, a broader range of cancers may possibly arise in MUTYH heterozygotes via a mechanism involving somatic LOH at the MUTYH locus and defective BER. However, the effect is modest and requires confirmation in additional studies before being clinically actionable

Repurposing Itraconazole as a Treatment for Advanced Prostate Cancer: A Noncomparative Randomized Phase II Trial in Men With Metastatic Castration‐Resistant Prostate Cancer

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139926/1/onco0163-sup-0001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139926/2/onco0163.pd

A Pilot Phase II Study of Digoxin in Patients with Recurrent Prostate Cancer as Evident by Rising PSA

Background: Digoxin was found to inhibit prostate cancer (PCa) growth via the inhibition of HIF-1α synthesis in a mouse model. We hypothesized that a therapeutic dose of digoxin could inhibit human PCa growth and disease progression. Methods: An open label, single arm pilot study was performed. Patients (pts) with non-metastatic, biochemically relapsed PCa with prostate specific antigen doubling time (PSADT) of 3 -24 months and no hormonal therapy within the past 6 months were enrolled. All pts had testosterone 50 ng/dL at baseline. Digoxin was taken daily with dose titration to achieve a target therapeutic level (0.8 – 2 ng/ml); patients had routine follow-up including cardiac monitoring with 12-lead electrocardiograms (ECGs) and digoxin levels. The primary endpoint was the proportion of pts at 6 months post-treatment with a PSADT 200% from the baseline. HIF-1α downstream molecule vascular endothelial growth factor (VEGF) was measured in plasma.Results: Sixteen pts were enrolled and 14 pts finished the planned 6 months of treatment. Twenty percent (3/15) of the pts had PSA decrease 25% from baseline with a medium duration of 14 months. At 6 months, 5 of 13 (38%) pts had PSADT 200% of the baseline PSADT and were continued on study for an additional 24 weeks of treatment. Two patients had durable PSA response for more than 1 year. Digoxin was well tolerated with possible relation of one grade 3 back pain. No patients had evidence of digoxin toxicity. The digoxin dose was lowered in 2 patients for significant ECGs changes (sinus bradycardia and QT prolongation), and there were probable digoxin-related ECG changes in 3 patients. Plasma VEGF was detected in 4 (25%) patients. Conclusions: Digoxin was well tolerated and showed a prolongation of PSDAT in 38% of the patients. However, there was no significant difference comparing that of similar patients on placebo from historical data. Digoxin at the dose used in this study may have limited benefit for patients with biochemically relapsed prostate cancer

Discordant and heterogeneous clinically relevant genomic alterations in circulating tumor cells vs plasma DNA from men with metastatic castration resistant prostate cancer

Circulating tumor cell (CTC) and cellâ free (cf) DNAâ based genomic alterations are increasingly being used for clinical decisionâ making in oncology. However, the concordance and discordance between paired CTC and cfDNA genomic profiles remain largely unknown. We performed comparative genomic hybridization (CGH) on CTCs and cfDNA, and lowâ pass whole genome sequencing (lpWGS) on cfDNA to characterize genomic alterations (CNA) and tumor content in two independent prospective studies of 93 men with mCRPC treated with enzalutamide/abiraterone, or radiumâ 223. Comprehensive analysis of 69 patient CTCs and 72 cfDNA samples from 93 men with mCRPC, including 64 paired samples, identified common concordant gains in FOXA1, AR, and MYC, and losses in BRCA1, PTEN, and RB1 between CTCs and cfDNA. Concordant PTEN loss and discordant BRCA2 gain were associated with significantly worse outcomes in Epic ARâ V7 negative men with mCRPC treated with abiraterone/enzalutamide. We identified and externally validated CTCâ specific genomic alternations that were discordant in paired cfDNA, even in samples with high tumor content. These CTC/cfDNAâ discordant regions included key genomic regulators of lineage plasticity, osteomimicry, and cellular differentiation, including MYCN gain in CTCs (31%) that was rarely detected in cfDNA. CTC MYCN gain was associated with poor clinical outcomes in ARâ V7 negative men and small cell transformation. In conclusion, we demonstrated concordance of multiple genomic alterations across CTC and cfDNA platforms; however, some genomic alterations displayed substantial discordance between CTC DNA and cfDNA despite the use of identical copy number analysis methods, suggesting tumor heterogeneity and divergent evolution associated with poor clinical outcomes.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153751/1/gcc22824.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153751/2/gcc22824_am.pd

Targeted Inhibition of CYP11A1 in Castration-Resistant Prostate Cancer

Targeted Inhibition of CYP11A1 in Prostate CancerIn this single-arm, multicenter, combined phase 1 and phase 2 study, patients with metastatic prostate adenocarcinoma with progression on prior androgen receptor pathway inhibitors and taxane-based chemotherapy were treated with ODM-208. A decrease in prostate-specific antigen levels of 50% or more occurred in 16/42 (38.1%) and 24/45 (53.3%) in phase 1 and 2 respectively. Responses mainly occurred in patients with androgen receptor mutations. Adrenal insufficiency was the dose-limiting toxicity.</p

Cabozantinib Versus Mitoxantrone-prednisone in Symptomatic Metastatic Castration-resistant Prostate Cancer: A Randomized Phase 3 Trial with a Primary Pain Endpoint

Background: Bone metastases in patients with metastatic castration-resistant prostate cancer (mCRPC) are associated with debilitating pain and functional compromise. Objective: To compare pain palliation as the primary endpoint for cabozantinib versus mitoxantrone-prednisone in men with mCRPC and symptomatic bone metastases using patient-reported outcome measures. Design, setting, and participants: A randomized, double-blind phase 3 trial (COMET-2; NCT01522443) in men with mCRPC and narcotic-dependent pain from bone metastases who had progressed after treatment with docetaxel and either abiraterone or enzalutamide. Intervention: Cabozantinib 60 mg once daily orally versus mitoxantrone 12 mg/m2 every 3 wk plus prednisone 5 mg twice daily orally. Outcome measurements and statistical analysis: The primary endpoint was pain response at week 6 confirmed at week 12 (≥30% decrease from baseline in patient-reported average daily worst pain score via the Brief Pain Inventory without increased narcotic use). The planned sample size was 246 to achieve ≥90% power. Results and limitations: Enrollment was terminated early because cabozantinib did not demonstrate any survival benefit in the companion COMET-1 trial. At study closure, 119 participants were randomized (cabozantinib: N =61; mitoxantrone-prednisone: N = 58). Complete pain and narcotic use data were available at baseline, week 6, and week 12 for 73/106 (69%) patients. There was no significant difference in the pain response with cabozantinib versus mitoxantrone-prednisone: the proportions of responders were 15%versus 17%,a −2%difference(95%confidenceinterval:−16%to11%, p = 0.8). Barriers to accrual included pretreatment requirements for a washout period of prior anticancer therapy and a narcotic optimization period to maximize analgesic dosing. Conclusions: Cabozantinib treatment did not demonstrate better pain palliation than mitoxantrone-prednisone in heavily pretreated patients with mCRPC and symptomatic bone metastases. Future pain-palliation trials should incorporate briefer timelines from enrollment to treatment initiation. Patient summary: Cabozantinib was not better than mitoxantrone-prednisone for pain relief in patients with castration-resistant prostate cancer and debilitating pain from bone metastases

T-Cell Infiltration and Adaptive Treg Resistance in Response to Androgen Deprivation With or Without Vaccination in Localized Prostate Cancer

Purpose: Previous studies suggest that androgen deprivation therapy (ADT) promotes antitumor immunity in prostate cancer. Whether a vaccine-based approach can augment this effect remains unknown. Experimental Design: Therefore, we conducted a neoadjuvant, randomized study to quantify the immunologic effects of a granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting allogeneic cellular vaccine in combination with low-dose cyclophosphamide (Cy/GVAX) followed by degarelix versus degarelix alone in patients with high-risk localized prostate adenocarcinoma who were planned for radical prostatectomy. Results: Both Cy/GVAX plus degarelix and degarelix alone led to significant increases in intratumoral CD8+ T cell infiltration and PD-L1 expression as compared to a cohort of untreated, matched controls. However, the CD8+ T cell infiltrate was accompanied by a proportional increase in regulatory T cells (Treg), suggesting that adaptive Treg resistance may dampen the immunogenicity of ADT. Although Cy/GVAX followed by degarelix was associated with a modest improvement in time-to-PSA progression and time-to-next treatment as well as an increase in PD-L1, there was no difference in the CD8 T-cell infiltrate as compared to degarelix alone. Gene expression profiling demonstrated that CHIT1, a macrophage marker, was differentially upregulated with Cy/GVAX plus degarelix compared to degarelix alone. Conclusions: Our results highlight that ADT with or without Cy/GVAX induces a complex immune response within the prostate tumor microenvironment. These data have important implications for combining ADT with immunotherapy. In particular, our finding that ADT increases both CD8+ T cells and Tregs, supports the development of regimens combining ADT with Treg-depleting agents in the treatment of prostate cancer

Definitions of disease burden across the spectrum of metastatic castration-sensitive prostate cancer: comparison by disease outcomes and genomics

BACKGROUND: Several definitions have attempted to stratify metastatic castrate-sensitive prostate cancer (mCSPC) into low and high-volume states. However, at this time, comparison of these definitions is limited. Here we aim to compare definitions of metastatic volume in mCSPC with respect to clinical outcomes and mutational profiles. METHODS: We performed a retrospective review of patients with biochemically recurrent or mCSPC whose tumors underwent somatic targeted sequencing. 294 patients were included with median follow-up of 58.3 months. Patients were classified into low and high-volume disease per CHAARTED, STAMPEDE, and two numeric (≤3 and ≤5) definitions. Endpoints including radiographic progression-free survival (rPFS), time to development of castration resistance (tdCRPC), and overall survival (OS) were evaluated with Kaplan-Meier survival curves and log-rank test. The incidence of driver mutations between definitions were compared. RESULTS: Median OS and tdCRPC were shorter for high-volume than low-volume disease for all four definitions. In the majority of patients (84.7%) metastatic volume classification did not change across all four definitions. High volume disease was significantly associated with worse OS for all four definitions (CHAARTED: HR 2.89; p < 0.01, STAMPEDE: HR 3.82; p < 0.01, numeric ≤3: HR 4.67; p < 0.01, numeric ≤5: HR 3.76; p < 0.01) however, were similar for high (p = 0.95) and low volume (p = 0.79) disease across all four definitions. Those with discordant classification tended to have more aggressive clinical behavior and mutational profiles. Patients with low-volume disease and TP53 mutation experienced a more aggressive course with rPFS more closely mirroring high-volume disease. CONCLUSIONS: The spectrum of mCSPC was confirmed across four different metastatic definitions for clinical endpoints and genetics. All definitions were generally similar in classification of patients, outcomes, and genetic makeup. Given these findings, the simplicity of numerical definitions might be preferred, especially when integrating metastasis directed therapy. Incorporation of tumor genetics may allow further refinement of current metastatic definitions