Up to 30% of patients with metastatic castration-resistant prostate cancer have deleterious mutations in genes involved in homologous recombination repair of DNA damage. The use of the PARP inhibitor ...olaparib in such patients was associated with longer progression-free survival and a longer time to pain progression than control therapy.
The PROfound trial showed that olaparib prolonged imaging-based progression-free survival among patients whose tumors contained defects in the homologous recombination repair genes
BRCA1
,
BRCA2
, or
...ATM
. With longer follow-up, the trial now shows that olaparib prolonged overall survival in these patients. Toxic effects included anemia, nausea, and asthenia.
Trials in castration-resistant prostate cancer (CRPC) need new clinical end points that are valid surrogates for survival. We evaluated circulating tumor cell (CTC) enumeration as a surrogate outcome ...measure.
Examining CTCs alone and in combination with other biomarkers as a surrogate for overall survival was a secondary objective of COU-AA-301, a multinational, randomized, double-blind phase III trial of abiraterone acetate plus prednisone versus prednisone alone in patients with metastatic CRPC previously treated with docetaxel. The biomarkers were measured at baseline and 4, 8, and 12 weeks, with 12 weeks being the primary measure of interest. The Prentice criteria were applied to test candidate biomarkers as surrogates for overall survival at the individual-patient level.
A biomarker panel using CTC count and lactate dehydrogenase (LDH) level was shown to satisfy the four Prentice criteria for individual-level surrogacy. Twelve-week surrogate biomarker data were available for 711 patients. The abiraterone acetate plus prednisone and prednisone-alone groups demonstrated a significant survival difference (P = .034); surrogate distribution at 12 weeks differed by treatment (P < .001); the discriminatory power of the surrogate to predict mortality was high (weighted c-index, 0.81); and adding the surrogate to the model eliminated the treatment effect on survival. Overall, 2-year survival of patients with CTCs < 5 (low risk) versus patients with CTCs ≥ 5 cells/7.5 mL of blood and LDH > 250 U/L (high risk) at 12 weeks was 46% and 2%, respectively.
A biomarker panel containing CTC number and LDH level was shown to be a surrogate for survival at the individual-patient level in this trial of abiraterone acetate plus prednisone versus prednisone alone for patients with metastatic CRPC. Additional trials are ongoing to validate the findings.
Summary Background Poly(ADP-ribose) polymerase (PARP) is implicated in DNA repair and transcription regulation. Niraparib (MK4827) is an oral potent, selective PARP-1 and PARP-2 inhibitor that ...induces synthetic lethality in preclinical tumour models with loss of BRCA and PTEN function. We investigated the safety, tolerability, maximum tolerated dose, pharmacokinetic and pharmacodynamic profiles, and preliminary antitumour activity of niraparib. Methods In a phase 1 dose-escalation study, we enrolled patients with advanced solid tumours at one site in the UK and two sites in the USA. Eligible patients were aged at least 18 years; had a life expectancy of at least 12 weeks; had an Eastern Cooperative Oncology Group performance status of 2 or less; had assessable disease; were not suitable to receive any established treatments; had adequate organ function; and had discontinued any previous anticancer treatments at least 4 weeks previously. In part A, cohorts of three to six patients, enriched for BRCA1 and BRCA2 mutation carriers, received niraparib daily at ten escalating doses from 30 mg to 400 mg in a 21-day cycle to establish the maximum tolerated dose. Dose expansion at the maximum tolerated dose was pursued in 15 patients to confirm tolerability. In part B, we further investigated the maximum tolerated dose in patients with sporadic platinum-resistant high-grade serous ovarian cancer and sporadic prostate cancer. We obtained blood, circulating tumour cells, and optional paired tumour biopsies for pharmacokinetic and pharmacodynamic assessments. Toxic effects were assessed by common toxicity criteria and tumour responses ascribed by Response Evaluation Criteria in Solid Tumors (RECIST). Circulating tumour cells and archival tumour tissue in prostate patients were analysed for exploratory putative predictive biomarkers, such as loss of PTEN expression and ETS rearrangements. This trial is registered with ClinicalTrials.gov , NCT00749502. Findings Between Sept 15, 2008, and Jan 14, 2011, we enrolled 100 patients: 60 in part A and 40 in part B. 300 mg/day was established as the maximum tolerated dose. Dose-limiting toxic effects reported in the first cycle were grade 3 fatigue (one patient given 30 mg/day), grade 3 pneumonitis (one given 60 mg/day), and grade 4 thrombocytopenia (two given 400 mg/day). Common treatment-related toxic effects were anaemia (48 patients 48%), nausea (42 42%), fatigue (42 42%), thrombocytopenia (35 35%), anorexia (26 26%), neutropenia (24 24%), constipation (23 23%), and vomiting (20 20%), and were predominantly grade 1 or 2. Pharmacokinetics were dose proportional and the mean terminal elimination half-life was 36·4 h (range 32·8–46·0). Pharmacodynamic analyses confirmed PARP inhibition exceeded 50% at doses greater than 80 mg/day and antitumour activity was documented beyond doses of 60 mg/day. Eight (40% 95% CI 19–64) of 20 BRCA1 or BRCA2 mutation carriers with ovarian cancer had RECIST partial responses, as did two (50% 7–93) of four mutation carriers with breast cancer. Antitumour activity was also reported in sporadic high-grade serous ovarian cancer, non-small-cell lung cancer, and prostate cancer. We recorded no correlation between loss of PTEN expression or ETS rearrangements and measures of antitumour activity in patients with prostate cancer. Interpretation A recommended phase 2 dose of 300 mg/day niraparib is well tolerated. Niraparib should be further assessed in inherited and sporadic cancers with homologous recombination DNA repair defects and to target PARP-mediated transcription in cancer. Funding Merck Sharp and Dohme.
In men with metastatic, hormone-sensitive prostate cancer who were receiving testosterone suppression, the addition of enzalutamide led to significantly longer progression-free and overall survival ...than the addition of standard nonsteroidal antiandrogen therapy. The better outcome was less clear among patients who had received docetaxel.
Purpose
We analysed quantitative biomarkers derived from both baseline whole-body imaging and blood serum to identify prognostic markers in patients treated within the lutetium-177 prostate-specific ...membrane antigen (LuPSMA) phase 2 trial.
Methods
PET image analysis was carried out using whole-body segmentation quantifying molecular tumour volume (SUV > 3 threshold for PSMA, SUV > liver+2sd for fluorodeoxyglucose (FDG) including SUVmax and SUVmean. For baseline bone scans, EXINI bone scan index (BSI) was used to calculate the percentage of involved bone. Baseline alkaline phosphatase (ALP), lactate dehydrogenase (LDH), prostate specific antigen (PSA) and PSA doubling time were also used in this analysis. We used univariate cox regression analysis and log-rank comparison with optimised cut-offs to find suitable biomarkers prognostic of overall survival from time of enrolment.
Results
This analysis identified FDG-positive tumour volume (FDGvol; HR 2.6; 95% CI, 1.4–4.8), mean intensity of PSMA-avid tumour uptake (PSMAmean; HR 0.89; 95% CI, 0.8–0.98), bone scan index (BSI; HR 2.3; 95% CI, 1.2–4.4), ALP (HR 1.1; 95% CI, 1–1.2) and LDH (HR 1.2; 95% CI, 1–1.5) as biomarkers prognostic of overall survival.
Conclusions
In addition to established biomarkers, both FDG and PSMA PET/CT parameters have prognostic significance for survival in men undergoing LuPSMA therapy.
Fourteen of 16 patients with metastatic, castration-resistant prostate cancer and genetic defects in repair of DNA damage had a response to the PARP inhibitor olaparib. Anemia and fatigue were the ...major toxic effects.
Prostate cancer is the most common cancer in men and the sixth leading cause of death from cancer among men throughout the world.
1
The interpatient molecular heterogeneity of this disease is well recognized; however, treatment to date has not been molecularly stratified.
2
,
3
It would be useful to identify predictive biomarkers in order to provide more precise treatment for this disease.
4
Metastatic, castration-resistant prostate cancer can have genomic aberrations that interfere with DNA repair.
3
,
5
Some of these aberrations have been associated with sensitivity to platinum and poly(adenosine diphosphate ADP–ribose) polymerase (PARP) inhibitors, suggesting that treatment with a PARP inhibitor . . .
Preclinical testing is a crucial step in evaluating cancer therapeutics. We aimed to establish a significant resource of patient-derived xenografts (PDXs) of prostate cancer for rapid and systematic ...evaluation of candidate therapies. The PDX collection comprises 59 tumors collected from 30 patients between 2012-2020, coinciding with availability of abiraterone and enzalutamide. The PDXs represent the clinico-pathological and genomic spectrum of prostate cancer, from treatment-naïve primary tumors to castration-resistant metastases. Inter- and intra-tumor heterogeneity in adenocarcinoma and neuroendocrine phenotypes is evident from bulk and single-cell RNA sequencing data. Organoids can be cultured from PDXs, providing further capabilities for preclinical studies. Using a 1 x 1 x 1 design, we rapidly identify tumors with exceptional responses to combination treatments. To govern the distribution of PDXs, we formed the Melbourne Urological Research Alliance (MURAL). This PDX collection is a substantial resource, expanding the capacity to test and prioritize effective treatments for prospective clinical trials in prostate cancer.
Loss of MHC class I (MHC-I) antigen presentation in cancer cells can elicit immunotherapy resistance. A genome-wide CRISPR/Cas9 screen identified an evolutionarily conserved function of polycomb ...repressive complex 2 (PRC2) that mediates coordinated transcriptional silencing of the MHC-I antigen processing pathway (MHC-I APP), promoting evasion of T cell-mediated immunity. MHC-I APP gene promoters in MHC-I low cancers harbor bivalent activating H3K4me3 and repressive H3K27me3 histone modifications, silencing basal MHC-I expression and restricting cytokine-induced upregulation. Bivalent chromatin at MHC-I APP genes is a normal developmental process active in embryonic stem cells and maintained during neural progenitor differentiation. This physiological MHC-I silencing highlights a conserved mechanism by which cancers arising from these primitive tissues exploit PRC2 activity to enable immune evasion.
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•PRC2 maintains bivalency at MHC-I antigen-processing genes silencing MHC-I expression•Cancer cells co-opt this conserved, lineage-specific PRC2 function to evade T cells•Pharmacological inhibition of PRC2 in MHC-I low cancers restores anti-tumor immunity•Immunotherapy resistance may arise via non-genomic routes that exploit PRC2 activity
Burr et al. show that cancer cells co-opt PRC2 to evade immune surveillance. PRC2 maintains bivalency at the promoters of MHC-I antigen-processing pathway (MHC-I APP) genes to repress their basal and cytokine-activated expression. Inhibition of PRC2 restores the MHC-I APP and T cell-mediated anti-tumor immunity.
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