Understanding lineage plasticity in prostate cancer cells is crucial to overcoming disease progression and therapeutic resistance. In this issue of Cancer Cell, Han et al. demonstrate that Foxa2 ...promotes luminal-to-neuroendocrine differentiation and that it also upregulates Kit expression in neuroendocrine cells. KIT signaling inhibition represents a promising therapeutic strategy in neuroendocrine prostate cancer.
Understanding lineage plasticity in prostate cancer cells is crucial to overcoming disease progression and therapeutic resistance. In this issue of Cancer Cell, Han et al. demonstrate that Foxa2 promotes luminal-to-neuroendocrine differentiation and that it also upregulates Kit expression in neuroendocrine cells. KIT signaling inhibition represents a promising therapeutic strategy in neuroendocrine prostate cancer.
Although novel agents targeting the androgen-androgen receptor (AR) axis have altered the treatment paradigm of metastatic castration-resistant prostate cancer (mCRPC), development of therapeutic ...resistance is inevitable. In this study, we examined whether AR gene aberrations detectable in circulating cell-free DNA (cfDNA) are associated with resistance to abiraterone acetate and enzalutamide in mCRPC patients.
Plasma was collected from 62 mCRPC patients ceasing abiraterone acetate (n = 29), enzalutamide (n = 19), or other agents (n = 14) due to disease progression. DNA was extracted and subjected to array comparative genomic hybridization (aCGH) for chromosome copy number analysis, and Roche 454 targeted next-generation sequencing of exon 8 in the AR.
On aCGH, AR amplification was significantly more common in patients progressing on enzalutamide than on abiraterone or other agents (53% vs. 17% vs. 21%, P = 0.02, χ(2)). Missense AR exon 8 mutations were detected in 11 of 62 patients (18%), including the first reported case of an F876L mutation in an enzalutamide-resistant patient and H874Y and T877A mutations in 7 abiraterone-resistant patients. In patients switched onto enzalutamide after cfDNA collection (n = 39), an AR gene aberration (copy number increase and/or an exon 8 mutation) in pretreatment cfDNA was associated with adverse outcomes, including lower rates of PSA decline ≥ 30% (P = 0.013, χ(2)) and shorter time to radiographic/clinical progression (P = 0.010, Cox proportional hazards regression).
AR gene aberrations in cfDNA are associated with resistance to enzalutamide and abiraterone in mCRPC. Our data illustrate that genomic analysis of cfDNA is a minimally invasive method for interrogating mechanisms of therapeutic resistance in mCRPC.
Abstract Background The activity of enzalutamide after prior treatment with both abiraterone acetate (abiraterone) and docetaxel has been examined in several retrospective studies. However, limited ...data are available on the efficacy of enzalutamide following abiraterone in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC). Objective To compare the activity of enzalutamide after abiraterone in docetaxel-experienced and docetaxel-naive mCRPC patients. Design, setting, and participants The British Columbia Cancer Agency Cancer Registry was searched for mCRPC patients who received enzalutamide after prior abiraterone. Clinicopathologic characteristics, confirmed prostate-specific antigen (PSA) response rates (PSA decline ≥50% confirmed ≥3 wk later), and survival data were collected. Outcome measurements and statistical analysis Outcomes on enzalutamide were compared between docetaxel-experienced and docetaxel-naive patients using chi-square for PSA response and log-rank test for time to PSA progression and overall survival (OS). Univariate analysis was performed to identify variables associated with confirmed PSA response on enzalutamide, using either chi-square for categorical variables or logistic regression for continuous variables. Results and limitations A total of 115 patients received enzalutamide after abiraterone: 68 had received prior docetaxel and 47 were docetaxel naive. Median time on enzalutamide was 4.1 mo. Confirmed PSA response rates (22% vs 26%; p = 0.8), median time to radiologic/clinical progression (4.6 mo vs 6.6 mo; p = 0.6), and median OS (10.6 mo vs 8.6 mo; p = 0.2) did not differ significantly between docetaxel-experienced and docetaxel-naive patients. No clinical variables (including prior response to abiraterone) were found to associate significantly with confirmed PSA response to enzalutamide. Conclusions Antitumour activity of enzalutamide following abiraterone was limited in mCRPC patients irrespective of prior docetaxel use. Identifying clinical and molecular factors predictive of response to enzalutamide remains a high priority for future research. Patient summary We looked at the effectiveness of enzalutamide after abiraterone acetate for treatment of advanced prostate cancer. We found that patients who had received docetaxel chemotherapy before abiraterone gained similar benefit from enzalutamide compared with patients who had not received docetaxel. These results suggest that earlier treatment with docetaxel does not have a large impact on the activity of enzalutamide after abiraterone.
The landscape of advanced prostate cancer treatment has evolved tremendously in past decades. The treatment paradigm has shifted from androgen deprivation therapy (ADT) alone to doublet combinations ...comprising ADT with docetaxel or an androgen receptor inhibitor, and now triplet therapy involving all 3 classes of agents. Robust clinical data has demonstrated survival benefits with this strategy of upfront treatment intensification. Subgroup analysis has alluded to the importance of tailoring treatment according to metastatic disease burden. However, defining the volume of disease is becoming increasingly controversial due to the advent of next generation molecular imaging. Several trials testing established agents in the castrate-resistant setting are now underway in metastatic hormone sensitive prostate cancer patients. As the treatment milieu is enriched earlier in the disease trajectory, future studies should elucidate biomarkers to further define specific patient populations who will benefit most from treatment intensification and/or de-escalation, with what agents and for what duration.
In patients with oligometastatic renal cell carcinoma, radiotherapy to all metastases followed by short-course pembrolizumab is safe, with a grade 3 adverse event rate of 13%. The combination is ...effective, with median progression-free survival of 15.6 mo and 2-yr local control of 92%.
Stereotactic ablative body radiotherapy (SABR) is an option for oligometastatic clear cell renal cell carcinoma (ccRCC) but is limited by a lack of prospective clinical trial data.
The RAPPORT trial evaluated the safety and efficacy of total metastatic irradiation followed by short-course anti–programmed death receptor-1 immunotherapy in patients with oligometastatic ccRCC.
RAPPORT was a single-arm multi-institutional phase I/II trial (NCT02855203). Patients with two or fewer lines of prior systemic therapy and one to five oligometastases from ccRCC were eligible.
A single fraction of 20 Gy SABR (or if not feasible, ten fractions of 3 Gy) was given to all metastatic sites, followed by pembrolizumab 200 mg administered Q3W for eight cycles.
The endpoints were adverse events (AEs), disease control rate (DCR) for at least 6 mo, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The Kaplan-Meier method was used for time-to-event endpoints. Freedom from local progression (FFLP) was assessed per lesion adding patient as a cluster effect.
Thirty evaluable patients, with a median age of 62 yr, were enrolled. The median follow-up was 28 mo. There were 44% of patients with intermediate-risk and 56% with favorable-risk disease. Eighty-three oligometastases were irradiated (median three per patient): eight adrenal, 11 bone, 43 lung, 12 lymph node, and nine soft tissue. Four patients (13%) had grade 3 treatment-related AEs: pneumonitis (n = 2), dyspnea (n = 1), and elevated alkaline phosphatase/alanine transaminase (n = 1). There were no grade 4 or 5 AEs. FFLP at 2 yr was 92%. ORR was 63% and DCR was 83%. Estimated 1- and 2-yr OS was 90% and 74%, respectively, and PFS was 60% and 45%, respectively. Limitations include a single-arm design and selected patient population.
SABR and short-course pembrolizumab in oligometastatic ccRCC is well tolerated, with excellent local control. Durable responses and encouraging PFS were observed, warranting further investigation.
The RAPPORT trial investigated the combination of high-dose precision radiotherapy and a short course of immunotherapy in patients with low-volume metastatic kidney cancer. We found that this treatment regimen was well tolerated, with excellent cancer control in sites of known disease. A proportion of patients were free from cancer relapse in the longer term, and these encouraging findings warrant further investigation.
Summary
Radiotherapy is an effective treatment modality commonly used in efforts to cure many localised cancers and in the palliation of symptoms in metastatic cancers.
Immunotherapy has ...revolutionised cancer care by increasing the disease control and overall survival of patients in several cancer types; however, the majority of patients do not respond to currently available therapies based on immune checkpoint inhibitors (ICIs). The benefit of those agents is limited to patients who have a pre‐existing active immune microenvironment that can be reactivated by ICIs.
It is now recognised that radiotherapy does not only directly kill tumour cells but it also changes the tumour microenvironment, enhancing tumour cell recognition by the immune system and, therefore, acting as an in situ vaccine.
Radiotherapy increases expression of tumour‐associated antigens, causes the release of cytokines, stimulates recruitment of dendritic cells and, most importantly, stimulates the proliferation and priming of cytotoxic CD8+ T cells in the tumour microenvironment. This immunological cascade specifically generates activated T cells able to induce immunogenic cell death directed against cancer cells bearing those antigens.
By its ability to overcome some tumour immune escape mechanisms, radiation provides a non‐pharmacological and cost‐effective approach to potentially improve the systemic response to immune checkpoints inhibitors.
Lutetium-177 177LuLu-PSMA-617 is a radiolabelled small molecule that delivers β radiation to cells expressing prostate-specific membrane antigen (PSMA), with activity and safety in patients with ...metastatic castration-resistant prostate cancer. We aimed to compare 177LuLu-PSMA-617 with cabazitaxel in patients with metastatic castration-resistant prostate cancer.
We did this multicentre, unblinded, randomised phase 2 trial at 11 centres in Australia. We recruited men with metastatic castration-resistant prostate cancer for whom cabazitaxel was considered the next appropriate standard treatment. Participants were required to have adequate renal, haematological, and liver function, and an Eastern Cooperative Oncology Group performance status of 0–2. Previous treatment with androgen receptor-directed therapy was allowed. Men underwent gallium-68 68GaGa-PSMA-11 and 2-flourine-1818Ffluoro-2-deoxy-D-glucose (FDG) PET-CT scans. PET eligibility criteria for the trial were PSMA-positive disease, and no sites of metastatic disease with discordant FDG-positive and PSMA-negative findings. Men were randomly assigned (1:1) to 177LuLu-PSMA-617 (6·0–8·5 GBq intravenously every 6 weeks for up to six cycles) or cabazitaxel (20 mg/m2 intravenously every 3 weeks for up to ten cycles). The primary endpoint was prostate-specific antigen (PSA) response defined by a reduction of at least 50% from baseline. This trial is registered with ClinicalTrials.gov, NCT03392428.
Between Feb 6, 2018, and Sept 3, 2019, we screened 291 men, of whom 200 were eligible on PET imaging. Study treatment was received by 98 (99%) of 99 men randomly assigned to 177LuLu-PSMA-617 versus 85 (84%) of 101 randomly assigned to cabazitaxel. PSA responses were more frequent among men in the 177LuLu-PSMA-617 group than in the cabazitaxel group (65 vs 37 PSA responses; 66% vs 37% by intention to treat; difference 29% (95% CI 16–42; p<0·0001; and 66% vs 44% by treatment received; difference 23% 9–37; p=0·0016). Grade 3–4 adverse events occurred in 32 (33%) of 98 men in the 177LuLu-PSMA-617 group versus 45 (53%) of 85 men in the cabazitaxel group. No deaths were attributed to 177LuLu-PSMA-617.
177LuLu-PSMA-617 compared with cabazitaxel in men with metastatic castration-resistant prostate cancer led to a higher PSA response and fewer grade 3 or 4 adverse events. 177LuLu-PSMA-617 is a new effective class of therapy and a potential alternative to cabazitaxel.
Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, The Distinguished Gentleman's Ride, It's a Bloke Thing, and CAN4CANCER.
JCO
In primary analysis, enzalutamide plus androgen deprivation therapy (ADT) improved radiographic progression-free survival (rPFS) in patients with metastatic hormone-sensitive prostate cancer ...(mHSPC); however, overall survival data were immature. In the phase III, double-blind, global ARCHES trial (ClinicalTrials.gov identifier: NCT02677896), 1,150 patients with mHSPC were randomly assigned 1:1 to enzalutamide (160 mg once daily) plus ADT or placebo plus ADT, stratified by disease volume and prior docetaxel use. Here, we report the final prespecified analysis of overall survival (key secondary end point) and an update on rPFS, other secondary end points, and safety. After unblinding, 180 (31.3%) progression-free patients randomly assigned to placebo plus ADT crossed over to open-label enzalutamide plus ADT. As of May 28, 2021 (median follow-up, 44.6 months), 154 of 574 patients randomly assigned to enzalutamide plus ADT and 202 of 576 patients randomly assigned to placebo plus ADT had died. Enzalutamide plus ADT reduced risk of death by 34% versus placebo plus ADT (median not reached in either group; hazard ratio, 0.66; 95% CI, 0.53 to 0.81;
< .001). Enzalutamide plus ADT continued to improve rPFS and other secondary end points. Adverse events were generally consistent with previous reports of long-term enzalutamide use. In conclusion, enzalutamide plus ADT significantly prolongs survival versus placebo plus ADT in patients with mHSPC.
Primary resistance to androgen receptor (AR)-directed therapies in metastatic castration-resistant prostate cancer (mCRPC) is poorly understood. We randomized 202 patients with treatment-naïve mCRPC ...to abiraterone or enzalutamide and performed whole-exome and deep targeted 72-gene sequencing of plasma cell-free DNA prior to therapy. For these agents, which have never been directly compared, time to progression was similar. Defects in
and
were strongly associated with poor clinical outcomes independently of clinical prognostic factors and circulating tumor DNA abundance. Somatic alterations in
, previously linked to reduced tumor dependency on AR signaling, were also independently associated with rapid resistance. Although detection of
amplifications did not outperform standard prognostic biomarkers,
gene structural rearrangements truncating the ligand binding domain were identified in several patients with primary resistance. These findings establish genomic drivers of resistance to first-line AR-directed therapy in mCRPC and identify potential minimally invasive biomarkers.
Leveraging plasma specimens collected in a large randomized phase II trial, we report the relative impact of common circulating tumor DNA alterations on patient response to the most widely used therapies for advanced prostate cancer. Our findings suggest that liquid biopsy analysis can guide the use of AR-targeted therapy in general practice.
.
PDF
![[177Lu]Lu-PSMA-617 versus c...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0140-6736/small "[177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial")
