Opinion statement
Due to its immunosuppressive tumor microenvironment, prostate cancer has historically been difficult to treat with immuno-oncology approaches. Other than pembrolizumab, which is now ...regulatory-approved for all microsatellite instability (MSI)-high and tumor mutational burden (TMB)-high advanced solid tumors, sipuleucel-T is the only immunotherapeutic agent approved by the US Food and Drug Administration (FDA) for prostate cancer. However, sipuleucel-T efficacy is optimal for select patients with indolent metastatic castration-resistant prostate cancer. Although manipulation of immune regulation by blocking immune checkpoints has led to substantial benefit in many cancers, experience with single-agent CTLA-4 and PD-1 or PD-L1 antibodies has shown limited effect for the majority of patients with prostate cancer, especially when administered as monotherapy. Combination therapies are now being attempted, in addition to enrichment strategies employing patient clinicopathologic and biologic characteristics that may heighten responses to immuno-oncology treatment, such as PD-L1 expression, TMB, MSI status, and alterations in
CDK12
. More work is needed to overcome the immune-exclusive barriers in prostate cancer, such as relatively low TMB, increased activity of myeloid-derived suppressor cells (MDSCs) and regulatory T cells, and defects in major histocompatibility complex (MHC) class I expression and interferon (IFN)-1 signaling. A promising approach and the likely next step in immuno-oncology for prostate cancer involves forced direction to markers expressed by prostate cancer tumor cells, such as prostate-specific membrane antigen (PSMA), that bypass the typical requirements for MHC class I interaction. The future will incorporate bispecific antibodies and chimeric antigen receptor (CAR)-T cells, potentially targeted towards phenotypic markers identified by next-generation PET imaging as part of the next wave of “precision medicine” in prostate cancer. Ultimately, we believe that the immune-exclusive prostate cancer tumor microenvironment can be overcome, and that patient outcomes can be enhanced through these more refined immuno-oncology approaches.
We evaluated the impact of the number of cycles of platinum based, first line chemotherapy (fewer than 6 cycles vs the conventional 6 cycles or more) on the survival of patients with metastatic ...urothelial carcinoma.
We used the RISC (Retrospective International Study of Invasive/Advanced Cancer of the Urothelium) database. The association of the number of cycles of chemotherapy with overall survival was investigated by Cox multiple regression analysis after controlling for recognized prognostic factors. We excluded patients who received fewer than 3 or more than 9 platinum chemotherapy cycles to reduce confounding factors. The primary analysis was a comparison of overall survival for 3 to 5 vs 6 to 9 cycles using 6-month landmark analysis when 281 death events were observed.
Of the 1,020 patients in the RISC 472 received cisplatin or carboplatin, of whom 338 and 134, respectively, were evaluable. A total of 157 patients received 3 to 5 cycles (median 4) and 315 received 6 to 9 cycles (median 6). There was no significant difference in overall survival between 3 to 5 and 6 to 9 cycles (HR 1.02, 95% CI 0.78–1.33, p = 0.91). No significant interactions were observed for the type of platinum (p = 0.09) and completed planned chemotherapy (p = 0.56). The limitations of a hypothesis generating, retrospective analysis applied.
Four cycles of platinum based, first line chemotherapy appeared adequate and did not significantly compromise the survival of patients with advanced urothelial carcinoma. The omission of excessive cycles may avoid unnecessary cumulative toxicity and facilitate a better transition to second line therapy and investigational switch maintenance therapy strategies. These results require prospective validation but they may impact practice in select patients.
There is an unmet need for therapeutic options that prolong survival for patients with heavily pretreated, metastatic castration-resistant prostate cancer (mCRPC). The phase III, open-label ...KEYLYNK-010 study evaluated pembrolizumab plus olaparib versus a next-generation hormonal agent (NHA) for biomarker-unselected, previously treated mCRPC.
Eligible participants had mCRPC that progressed on or after abiraterone or enzalutamide (but not both) and docetaxel. Participants were randomly assigned (2:1) to pembrolizumab plus olaparib or NHA (abiraterone or enzalutamide). The dual primary end points were radiographic progression-free survival (rPFS) by blinded independent central review per Prostate Cancer Working Group-modified RECIST 1.1 and overall survival (OS). Time to first subsequent therapy (TFST) was a key secondary end point. Safety and objective response rate (ORR) were secondary end points.
Between May 30, 2019, and July 16, 2021, 529 participants were randomly assigned to pembrolizumab plus olaparib and 264 to NHA. At final rPFS analysis, median rPFS was 4.4 months (95% CI, 4.2 to 6.0) with pembrolizumab plus olaparib and 4.2 months (95% CI, 4.0 to 6.1) with NHA (hazard ratio HR, 1.02 95% CI, 0.82 to 1.25;
= .55). At final OS analysis, median OS was 15.8 months (95% CI, 14.6 to 17.0) and 14.6 months (95% CI, 12.6 to 17.3), respectively (HR, 0.94 95% CI, 0.77 to 1.14;
= .26). At final TFST analysis, median TFST was 7.2 months (95% CI, 6.7 to 8.1) versus 5.7 months (95% CI, 5.0 to 7.1), respectively (HR, 0.86 95% CI, 0.71 to 1.03). ORR was higher with pembrolizumab plus olaparib versus NHA (16.8%
5.9%). Grade ≥3 treatment-related adverse events occurred in 34.6% and 9.0% of participants, respectively.
Pembrolizumab plus olaparib did not significantly improve rPFS or OS versus NHA in participants with biomarker-unselected, heavily pretreated mCRPC. The study was stopped for futility. No new safety signals occurred.
Genome-wide genetic approaches have proven useful for examining pathways of biological significance in model organisms such as Saccharomyces cerevisiae, Drosophila melanogastor, and Caenorhabditis ...elegans, but similar techniques have proven difficult to apply to mammalian systems. Although manipulation of the murine genome has led to identification of genes and their function, this approach is laborious, expensive, and often leads to lethal phenotypes. RNA interference (RNAi) is an evolutionarily conserved process of gene silencing that has become a powerful tool for investigating gene function by reverse genetics. Here we describe the delivery of cassettes expressing hairpin RNA targeting green fluorescent protein (GFP) using Moloney leukemia virus-based and lentivirus-based retroviral vectors. Both transformed cell lines and primary dendritic cells, normally refractory to transfection-based gene transfer, demonstrated stable silencing of targeted genes, including the tumor suppressor gene TP53 in normal human fibroblasts. This report demonstrates that both Moloney leukemia virus and lentivirus vector-mediated expression of RNAi can achieve effective, stable gene silencing in diverse biological systems and will assist in elucidating gene functions in numerous cell types including primary cells.
Cell-free DNA (cfDNA) testing is increasingly used in the treatment of patients with advanced prostate cancer. Clonal hematopoiesis of indeterminate potential (CHIP) can interfere with cfDNA testing ...and cause incorrect interpretation of results. There is an urgent need to better understand this problem following recent US Food and Drug Administration approval of poly(ADP) ribose polymerase inhibitors (PARPi) for metastatic prostate cancer based on variants in DNA repair genes that can be affected by CHIP.
To determine the prevalence of clinically relevant CHIP interference in prostate cancer cfDNA testing.
We report a case series of 69 patients with advanced prostate cancer (metastatic disease or with rising PSA following localized therapy) who had cfDNA variant testing with a large panel cancer next generation sequencing assay (UW-OncoPlexCT). To determine the source of variants in plasma, we tested paired cfDNA and whole blood control samples. The study was carried out in an academic medical center system reference laboratory.
Prevalence and gene spectrum of CHIP interference in patients with prostate cancer undergoing cfDNA testing.
We detected CHIP variants at 2% or more variant fraction in cfDNA from 13 of 69 men with prostate cancer (19%; 95% CI, 10%-30%). Seven men (10%; 95% CI, 4%-20%) had CHIP variants in DNA repair genes used to determine PARPi candidacy, including ATM (n = 5), BRCA2 (n = 1), and CHEK2 (n = 1). Overall, CHIP variants accounted for almost half of the somatic DNA repair gene variants detected. Participant CHIP variants were exponentially correlated with older age (R2 = 0.82). CHIP interference variants could be distinguished from prostate cancer variants using a paired whole-blood control.
In this case series, approximately 10% of men with advanced prostate cancer had CHIP interference in plasma cfDNA in DNA repair genes that are used for eligibility of PARPi therapy, most frequently in ATM. Clinical cfDNA testing should include a paired whole-blood control to exclude CHIP variants and avoid misdiagnosis.
The KEYNOTE-365 study assessed the efficacy and safety of pembrolizumab combination therapies in metastatic castration-resistant prostate cancer (mCRPC). In cohort A, pembrolizumab plus olaparib ...showed antitumor activity and manageable safety in patients with molecularly unselected, docetaxel-pretreated mCRPC.
Pembrolizumab and olaparib have shown single-agent activity in patients with previously treated metastatic castration-resistant prostate cancer (mCRPC).
To evaluate the efficacy and safety of pembrolizumab plus olaparib in mCRPC.
Cohort A of the phase 1b/2 KEYNOTE-365 study enrolled patients with molecularly unselected, docetaxel-pretreated mCRPC whose disease progressed within 6 mo of screening.
Pembrolizumab 200 mg intravenously every 3 wk plus olaparib 400-mg capsule or 300-mg tablet orally twice daily.
The primary endpoints were safety, confirmed prostate-specific antigen (PSA) response rate, and objective response rate (ORR) as per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, by blinded independent central review. The secondary endpoints included radiographic progression-free survival (rPFS) and overall survival (OS).
Of 104 enrolled patients, 102 were treated. The median age was 70 yr (interquartile range IQR, 65–76), and 59 patients (58%) had measurable disease as per RECIST v1.1. The median time from the first dose to database cutoff was 24 mo (IQR, 22–47). The confirmed PSA response rate was 15%. The confirmed ORR was 8.5% (five partial responses) for patients with measurable disease. The median rPFS was 4.5 mo (95% confidence interval CI, 4.0–6.5) and median OS was 14 mo (95% CI, 10.4–18.2). Clinical activity was consistent across the programmed death ligand 1 (PD-L1)-positive and homologous recombination repair mutation subgroups. Treatment-related adverse events (TRAEs) occurred in 93 patients (91%). Grade 3–5 TRAEs occurred in 49 patients (48%). Six deaths (5.9%) were due to adverse events; two (myocardial infarction and unknown cause) were attributed to treatment. Limitations of the study include the single-arm design.
Pembrolizumab plus olaparib had a safety profile consistent with the profiles of the individual agents and demonstrated antitumor activity in previously treated patients with molecularly unselected, docetaxel-pretreated mCRPC.
Pembrolizumab plus olaparib showed antitumor activity and expected safety in patients with metastatic castration-resistant prostate cancer.
Abstract Background Phosphatidylinositol-3-kinase (PI3K) and androgen receptor pathway activation is common in metastatic castration resistant prostate cancer (mCRPC). Buparlisib is an oral, ...pan-class I PI3 kinase inhibitor. Methods This was a multisite single arm phase II trial of buparlisib 100 mg ± enzalutamide daily in men with mCRPC whose disease progressed on or who were not candidates for docetaxel. The primary end-point was the rate of radiographic/clinical progression-free survival (PFS) at 6 months. Results Thirty men were accrued: 67% post-docetaxel; median prostate specific antigen (PSA) was 70 ng/dl, 83% had ≥4 prior therapies for mCRPC; 43% received concurrent enzalutamide. The final 6 month PFS rate was estimated to be 10% (95% confidence interval 2.5–23.6%). Median PFS was 1.9 months and was 3.5 months with concurrent enzalutamide. Median overall survival was 10.6 months. Concurrent enzalutamide led to a five-fold reduction in buparlisib concentrations. PSA declines were observed in 23%; no patients achieved a ≥50% decline, and no radiographic responses were observed. Severe adverse events occurred in four men including respiratory infection and multi-organ failure, urinary tract obstruction, confusion and one seizure in the setting of a new central nervous system (CNS) metastasis. Grade III adverse events were seen in 43% of patients; common toxicities included grade I–II weight loss, diarrhoea, nausea, fatigue, anorexia, rash, hyperglycemia and anxiety/mood disorders. Conclusions Buparlisib did not demonstrate significant activity in men with mCRPC, suggesting that PI3K inhibition is not sufficient to reverse resistant mCRPC progression. Future studies of PI3K pathway inhibitors with concurrent enzalutamide should develop optimal dosing and focus on selected patients more likely to benefit.
The KEYNOTE-365 study assessed the efficacy and safety of pembrolizumab combination therapies in metastatic castration-resistant prostate cancer pretreated with abiraterone or enzalutamide. In cohort ...B of the study, pembrolizumab plus docetaxel and prednisone showed clinical benefit with manageable safety.
Patients with metastatic castration-resistant prostate cancer (mCRPC) frequently receive docetaxel after they develop resistance to abiraterone or enzalutamide and need more efficacious treatments.
To evaluate the efficacy and safety of pembrolizumab plus docetaxel and prednisone in patients with mCRPC.
The trial included patients with mCRPC in the phase 1b/2 KEYNOTE-365 cohort B study who were chemotherapy naïve and who experienced failure of or were intolerant to ≥4 wk of abiraterone or enzalutamide for mCRPC with progressive disease within 6 mo of screening.
Pembrolizumab 200 mg intravenously (IV) every 3 wk (Q3W), docetaxel 75 mg/m2 IV Q3W, and prednisone 5 mg orally twice daily.
The primary endpoints were safety, the prostate-specific antigen (PSA) response rate, and the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by blinded independent central review (BICR). Secondary endpoints included time to PSA progression; the disease control rate (DCR) and duration of response (DOR) according to RECIST v1.1 by BICR; ORR, DCR, DOR, and radiographic progression-free survival (rPFS) according to Prostate Cancer Working Group 3–modified RECIST v1.1 by BICR; and overall survival (OS).
Among 104 treated patients, 52 had measurable disease. The median time from allocation to data cutoff (July 9, 2020) was 32.4 mo, during which 101 patients discontinued treatment, 81 (78%) for disease progression. The confirmed PSA response rate was 34% and the confirmed ORR (RECIST v1.1) was 23%. Median rPFS and OS were 8.5 mo and 20.2 mo, respectively. Treatment-related adverse events (TRAEs) occurred in 100 patients (96%). Grade 3–5 TRAEs occurred in 46 patients (44%). Seven AE-related deaths (6.7%) occurred (2 due to treatment-related pneumonitis). Limitations of the study include the single-arm design and small sample size.
Pembrolizumab plus docetaxel and prednisone demonstrated antitumor activity in chemotherapy-naïve patients with mCRPC treated with abiraterone or enzalutamide for mCRPC. Safety was consistent with profiles for the individual agents. Further investigation is warranted.
We evaluated the efficacy and safety of the anti-PD-1 antibody pembrolizumab combined with the chemotherapy drug docetaxel and the steroid prednisone for patients with metastatic prostate cancer resistant to androgen deprivation therapy , and who never received chemotherapy. The combination showed antitumor activity and manageable safety in this patient population.
This trial is registered on ClinicalTrials.gov as NCT02861573.
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