Background
Currently, there is no universally accepted prognostic classification for patients (pts) with metastatic hormone sensitive prostate cancer (mHSPC) treated with androgen deprivation therapy ...(ADT). Subgroup analyses demonstrated that pts with low volume (LV), per CHAARTED trial definition, mHSPC, and those who relapse after prior local therapy (PLT) have longer overall survival (OS) compared to high volume (HV) and de‐novo (DN), respectively. Using a hospital‐based registry, we aimed to assess whether a classification based on time of metastatic disease (PLT vs DN) and disease volume (LV vs HV) are prognostic for mHSPC pts treated with ADT.
Methods
A retrospective cohort of consecutive patients with mHSPC treated with ADT between 1990 and 2013 was selected from the prospectively collected Dana‐Farber Cancer Institute database and categorized as DN or PLT and HV or LV, at time of ADT start. Primary and secondary endpoints were OS and time to castration‐resistant prostate cancer (CRPC), respectively, which were measured from date of ADT start using Kaplan‐Meier method. Multivariable Cox proportional hazards models using known prognostic factors was used.
Results
The analytical cohort consisted of 436 patients. The median OS and time to CRPC for PLT/LV were 92.4 (95%CI: 80.4‐127.2) and 25.6 (95%CI: 21‐35.7) months and 43.2 (95%CI: 37.2‐56.4) and 12.2 (95%CI: 9.8‐14.8) months for DN/HV, respectively, whereas intermediate values were observed for PLT/HV and DN/LV. A robust gradient for both outcomes was observed (Trend test P < 0.0001) in the four groups. In a multivariable analysis, DN presentation, HV, and cancer‐related pain were independent prognostic factors.
Conclusions
In our hospital‐based registry, time of metastatic presentation and disease volume were prognostic for mHSPC pts treated with ADT. This simple prognostic classification system can aid patient counseling and future trial design.
Programmed cell death ligand-1 (PD-L1)/programmed cell death-1 (PD-1) blockade has been unsuccessful in prostate cancer, with poor immunogenicity and subsequent low PD-L1 expression in prostate ...cancer being proposed as an explanation. However, recent studies indicate that a subset of prostate cancer may express significant levels of PD-L1. Furthermore, the androgen antagonist enzalutamide has been shown to upregulate PD-L1 expression in prostate cancer preclinical models. In this study, we evaluated the effect of neoadjuvant androgen deprivation therapy with abiraterone acetate plus prednisone and leuprolide (Neo-AAPL) on PD-L1 expression in prostate cancer.
Radical prostatectomy (RP) tissues were collected from 44 patients with intermediate- to high-risk prostate cancer who underwent RP after Neo-AAPL treatment. Untreated prostate cancer tissues were collected from 130 patients, including 44 matched controls for the Neo-AAPL cases. Tumor PD-L1 expression was detected by IHC using validated anti-PD-L1 antibodies. Tumor-infiltrating CD8
cells were analyzed in trial cases and matched controls. Expression of DNA mismatch repair genes was examined in PD-L1-positive tumors.
Neo-AAPL-treated tumors showed a trend toward decreased PD-L1 positivity compared with matched controls (7% vs. 21% having ≥1% positive tumor cells;
= 0.062). Treated tumors also harbored significantly fewer tumor-infiltrating CD8
cells (
= 0.029). In 130 untreated prostate cancers, African American ethnicity, elevated serum PSA, and small prostate independently predicted tumor PD-L1 positivity. Loss of MSH2 expression was observed in 1 of 21 PD-L1-positive tumors.
A subset of prostate cancer expresses PD-L1, which is not increased by Neo-AAPL treatment, indicating that combining Neo-AAPL treatment with PD-L1/PD-1 blockade may not be synergistic.
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In a study involving nearly 1200 men with metastatic prostate cancer who had progressive disease after chemotherapy, enzalutamide, a novel androgen-receptor blocker, extended the median survival by ...nearly 5 months, as compared with placebo (18 months vs. 13 months).
Prostate cancer is an androgen-dependent disease that initially responds but later becomes resistant to established therapies that reduce circulating testosterone levels or inhibit androgen binding to the androgen receptor.
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Reactivation of the disease despite castrate levels of testosterone represents a transition to the lethal phenotype of castration-resistant prostate cancer.
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This state was previously called androgen-independent or hormone-refractory prostate cancer but is now recognized to be driven by androgen-receptor signaling, in part due to overexpression of the androgen receptor itself.
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In preclinical models of prostate cancer, androgen-receptor overexpression shortens the period of tumor latency and confers resistance to . . .
Background
We sought to describe patterns of delivery of adjuvant (aRT) and salvage RT (sRT) in patients who underwent RP after receiving neoadjuvant androgen receptor pathway inhibitor (ARPI) before ...radical prostatectomy (RP) for high‐risk localized prostate cancer (HRLPC).
Methods
Two hundred eighteen patients treated on phase 2 neoadjuvant trials between 2006 and 2018 at two academic centers were evaluated. aRT and sRT were defined as receipt of RT with a PSA of ≤0.1 or >0.1 ng/mL, respectively. Primary outcomes were biochemical recurrence (BCR), defined as time from aRT/sRT to a PSA rising to >0.1 ng/mL, and metastasis‐free survival (MFS) after RT.
Results
Twenty‐three (11%) and 55 (25%) patients received aRT and sRT respectively. Median PSA at start of aRT and sRT was 0.01 and 0.16 ng/mL, and median duration from RP to RT was 5 and 14 months, respectively. All aRT patients had NCCN high‐risk disease, 30% were pN1 and 43% had positive surgical margins; 52% had prostate bed RT. Fifty‐one percent of sRT patients had biopsy Gleason 9–10, 29% were pT2 and 9% had positive surgical margins; 63% had RT to the prostate bed/pelvis. At a median follow‐up of 5.3 and 3.0 years after aRT and sRT, 3‐year freedom from BCR was 55% and 47%, and 3‐year MFS was 56% and 53%, respectively.
Conclusions
aRT was infrequently used in patients who received neoadjuvant ARPI before RP for HRLPC. Outcomes of aRT and sRT were similar but generally poor. Studies evaluating intensified systemic therapy approaches with postoperative RT in this high‐risk population are needed.
Nearly all prostate cancer deaths are from metastatic castration-resistant prostate cancer (mCRPC), but there have been few whole-genome sequencing (WGS) studies of this disease state. We performed ...linked-read WGS on 23 mCRPC biopsy specimens and analyzed cell-free DNA sequencing data from 86 patients with mCRPC. In addition to frequent rearrangements affecting known prostate cancer genes, we observed complex rearrangements of the AR locus in most cases. Unexpectedly, these rearrangements include highly recurrent tandem duplications involving an upstream enhancer of AR in 70%–87% of cases compared with <2% of primary prostate cancers. A subset of cases displayed AR or MYC enhancer duplication in the context of a genome-wide tandem duplicator phenotype associated with CDK12 inactivation. Our findings highlight the complex genomic structure of mCRPC, nominate alterations that may inform prostate cancer treatment, and suggest that additional recurrent events in the non-coding mCRPC genome remain to be discovered.
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•Linked-read genome sequencing of mCRPC resolves haplotypes and rearrangements•CDK12 inactivation is associated with a global tandem duplication phenotype•A majority of cases have duplications of an enhancer of the androgen receptor•Progression on androgen pathway inhibitors is associated with gains in AR and AR enhancer
Linked-read genome sequencing data from patients highlight that amplification of an enhancer upstream of the androgen receptor locus is a key feature of metastatic castration-resistant prostate cancer.
Functional androgen receptor (AR) signaling is necessary for the development of prostate cancer. The therapeutic effect of androgen deprivation therapy for prostate cancer was described over 60 years ...ago and this treatment remains the mainstay of systemic therapy despite its transient response duration. It has become clear that AR expression and signaling remains intact as the disease evolves from androgen-sensitive cancer to classically (but perhaps inaccurately) termed hormone refractory prostate cancer. Through several genetic and epigenetic adaptations, prostate tumors continue to rely on AR growth signaling and they thus remain targets of 'hormonal' therapy. The development of new strategies and drugs that can abrogate AR signaling will probably result in important clinical benefits. The biology of androgen independence and the development of new approaches targeting AR signaling are reviewed herein.
Abiraterone blocks androgen synthesis and prolongs survival in patients with castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis. Abiraterone is ...metabolized in patients to Δ(4)-abiraterone (D4A), which has even greater anti-tumour activity and is structurally similar to endogenous steroidal 5α-reductase substrates, such as testosterone. Here, we show that D4A is converted to at least three 5α-reduced and three 5β-reduced metabolites in human serum. The initial 5α-reduced metabolite, 3-keto-5α-abiraterone, is present at higher concentrations than D4A in patients with prostate cancer taking abiraterone, and is an androgen receptor agonist, which promotes prostate cancer progression. In a clinical trial of abiraterone alone, followed by abiraterone plus dutasteride (a 5α-reductase inhibitor), 3-keto-5α-abiraterone and downstream metabolites were depleted by the addition of dutasteride, while D4A concentrations rose, showing that dutasteride effectively blocks production of a tumour-promoting metabolite and permits D4A accumulation. Furthermore, dutasteride did not deplete the three 5β-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacological 5α-reductase inhibition on abiraterone metabolism. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine-tuning abiraterone metabolism to optimize therapy.
Purpose Enzalutamide resistance could result from raised androgens and be overcome by combination with abiraterone acetate. PLATO ( ClinicalTrials.gov identifier: NCT01995513) interrogated this ...hypothesis using a randomized, double-blind, placebo-controlled design. Patients and Methods In period one, men with chemotherapy-naïve metastatic castration-resistant prostate cancer received open-label enzalutamide 160 mg daily. Men with no prostate-specific antigen (PSA) increase at weeks 13 and 21 were treated until PSA progression (≥ 25% increase and ≥ 2 ng/mL above nadir), then randomly assigned at a one-to-one ratio in period two to abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily with either enzalutamide or placebo (combination or control group, respectively) until disease progression as defined by the primary end point: progression-free survival (radiographic or unequivocal clinical progression or death during study). Secondary end points included time to PSA progression and PSA response in period two. Results Of 509 patients enrolled in period one, 251 were randomly assigned in period two. Median progression-free survival was 5.7 months in the combination group and 5.6 months in the control group (hazard ratio, 0.83; 95% CI, 0.61 to 1.12; P = .22). There was no difference in the secondary end points. Grade 3 hypertension (10% v 2%) and increased ALT (6% v 2%) or AST (2% v 0%) were more frequent in the combination than the control group. Conclusion Combining enzalutamide with abiraterone acetate and prednisone is not indicated after PSA progression during treatment with enzalutamide alone; hypertension and elevated liver enzymes are more frequent with combination therapy.
Summary Background Abiraterone acetate plus prednisone significantly improved radiographic progression-free survival compared with placebo plus prednisone in men with chemotherapy-naive ...castration-resistant prostate cancer at the interim analyses of the COU-AA-302 trial. Here, we present the prespecified final analysis of the trial, assessing the effect of abiraterone acetate plus prednisone on overall survival, time to opiate use, and use of other subsequent therapies. Methods In this placebo-controlled, double-blind, randomised phase 3 study, 1088 asymptomatic or mildly symptomatic patients with chemotherapy-naive prostate cancer stratified by Eastern Cooperative Oncology performance status (0 vs 1) were randomly assigned with a permuted block allocation scheme via a web response system in a 1:1 ratio to receive either abiraterone acetate (1000 mg once daily) plus prednisone (5 mg twice daily; abiraterone acetate group) or placebo plus prednisone (placebo group). Coprimary endpoints were radiographic progression-free survival and overall survival analysed in the intention-to-treat population. The study is registered with ClinicalTrials.gov , number NCT00887198. Findings At a median follow-up of 49·2 months (IQR 47·0–51·8), 741 (96%) of the prespecified 773 death events for the final analysis had been observed: 354 (65%) of 546 patients in the abiraterone acetate group and 387 (71%) of 542 in the placebo group. 238 (44%) patients initially receiving prednisone alone subsequently received abiraterone acetate plus prednisone as crossover per protocol (93 patients) or as subsequent therapy (145 patients). Overall, 365 (67%) patients in the abiraterone acetate group and 435 (80%) in the placebo group received subsequent treatment with one or more approved agents. Median overall survival was significantly longer in the abiraterone acetate group than in the placebo group (34·7 months 95% CI 32·7–36·8 vs 30·3 months 28·7–33·3; hazard ratio 0·81 95% CI 0·70–0·93; p=0·0033). The most common grade 3–4 adverse events of special interest were cardiac disorders (41 8% of 542 patients in the abiraterone acetate group vs 20 4% of 540 patients in the placebo group), increased alanine aminotransferase (32 6% vs four <1%), and hypertension (25 5% vs 17 3%). Interpretation In this randomised phase 3 trial with a median follow-up of more than 4 years, treatment with abiraterone acetate prolonged overall survival compared with prednisone alone by a margin that was both clinically and statistically significant. These results further support the favourable safety profile of abiraterone acetate in patients with chemotherapy-naive metastatic castration-resistant prostate cancer. Funding Janssen Research & Development.
The Gleason score is the best independent predictor of prostate cancer outcomes.1 The principle distinction between Gleason 6 disease vs Gleason 7 to 10 disease is that Gleason 6 disease does not ...necessarily need definitive treatment.2 Nevertheless, the implications of Gleason score are less clear in black men because of disparate prostate cancer outcomes, particularly for Gleason 6 disease, in which risk assessment and management of disease in black men is controversial.2,3 We investigated prostate cancer–specific mortality by Gleason score and race.
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