Sipuleucel-T (PROVENGE; Dendreon) is the first therapeutic cancer vaccine to be approved by the U.S. Food and Drug Administration. In men who have metastatic castration-resistant prostate cancer with ...no or minimal symptoms, sipuleucel-T prolongs median survival by 4.1 months compared with results in those treated with placebo. At 3 years, the proportion of patients in the vaccine group who were alive was 50% higher than that in the control group (31.7% versus 21.7%, respectively). Sipuleucel-T, which is designed to elicit an immune response to prostatic acid phosphatase, uses the patient's own immune system to recognize and combat his cancer. Currently, no other agents are available that offer a survival benefit for this population of asymptomatic patients who have not been treated with chemotherapy, except for docetaxel (whose inherent toxicities often lead patients and physicians to delay administration until symptoms develop). Straightforward strategies to increase the efficacy of sipuleucel-T are likely to provide even greater benefit. The preclinical and clinical development of sipuleucel-T is reviewed, and approaches to enhance efficacy are considered herein.
In this review, we address adherence rates in clinical settings, barriers to compliance with dosing schedules, and potential strategies to overcome challenges in maintaining high levels of adherence.
...Four studies reporting real-world adherence to prostate cancer medications, 52 studies describing barriers to adherence, and 16 studies on methods to minimize poor adherence were reviewed.
Mean nonadherence rates of 25% to 51% have been identified in prostate cancer patients prescribed oral therapies, with higher rates in older patients. An extensive review of prostate cancer patients receiving gonadotropin hormone-releasing hormone agonist injections found an overall nonadherence rate of over 27%. Patients may encounter barriers to complying with dosing instructions related to the medication (eg, complex dosing schedules, the total burden of medication management, fasting or dietary requirements, high medication costs, adverse effects, and drug-drug interactions). Barriers may also be related to patient-specific factors (eg, suboptimal education regarding the importance of adherence, physical limitations and cognitive decline associated with advancing age, living alone without a care partner, high symptom burden, needle phobia, and comorbid mental disorders). Interventions to improve dosing adherence may include automated reminders, treatment diaries, educational materials, and the involvement of patients, family members, care partners, and health care teams.
Many oral anticancer medications improve survival in men with prostate cancer, and therefore it is vital to establish good adherence by understanding the pitfalls that patients may encounter. In situations where both oral and injectable drugs are interchangeable, injections of long-acting drugs lead to fewer opportunities for dosing nonadherence than oral therapies. In contrast, oral medicines do not require scheduling for injections and travel for injection appointments. Therefore, maximizing adherence to all treatment regimens will reduce the chance of efficacy failures and likely lead to improved clinical outcomes.
Enzalutamide, a potent oral androgen receptor inhibitor, improves survival in men with metastatic castration-resistant prostate cancer (CRPC) before and after chemotherapy. Bicalutamide, a ...nonsteroidal antiandrogen, is widely used to treat men with nonmetastatic or metastatic CRPC. The efficacy and safety of these drugs were compared in this randomized, double-blind, phase II study of men with CRPC.
A total of 396 men with nonmetastatic (n = 139) or metastatic (n = 257) CRPC were randomly assigned to enzalutamide 160 mg per day (n = 198) or bicalutamide 50 mg per day (n = 198). Androgen deprivation therapy was continued in both arms. The primary end point was progression-free survival (PFS).
Enzalutamide reduced the risk of progression or death by 76% compared with bicalutamide (hazard ratio HR, 0.24; 95% CI, 0.18 to 0.32; P < .001). Median PFS was 19.4 months with enzalutamide versus 5.7 months with bicalutamide. Enzalutamide resulted in significant improvements in all key secondary end points: time to prostate-specific antigen progression (HR, 0.19; 95% CI, 0.14 to 0.26; P < .001); proportion of patients with a ≥ 50% prostate-specific antigen response (81% v 31%; P < .001); and radiographic PFS in metastatic patients (HR, 0.32; 95% CI, 0.21 to 0.50; P < .001). Beneficial effects with enzalutamide were observed in both nonmetastatic and metastatic subgroups. The observed adverse event profile was consistent with that from phase III enzalutamide trials.
Enzalutamide significantly reduced risk of prostate cancer progression or death compared with bicalutamide in patients with nonmetastatic or metastatic CRPC.
Genomic alterations in DNA damage repair (DDR) genes other than
may confer synthetic lethality with PARP inhibition in metastatic castration-resistant prostate cancer (mCRPC). To test this ...hypothesis, the phase II TRITON2 study of rucaparib included patients with mCRPC and deleterious non-
DDR gene alterations.
TRITON2 enrolled patients who had progressed on one or two lines of next-generation androgen receptor-directed therapy and one taxane-based chemotherapy for mCRPC. Key endpoints were investigator-assessed radiographic response per modified RECIST/PCWG3 and PSA response (≥50% decrease from baseline).
TRITON2 enrolled 78 patients with a non-
DDR gene alteration
(
= 49),
(
= 15),
(
= 12), and other DDR genes (
= 14). Among patients evaluable for each endpoint, radiographic and PSA responses were observed in a limited number of patients with an alteration in
2/19 (10.5%) and 2/49 (4.1%), respectively,
0/10 (0%) and 1/15 (6.7%), respectively, or
1/9 (11.1%) and 2/12 (16.7%), respectively, including no radiographic or PSA responses in 11 patients with confirmed biallelic
loss or 11 patients with
germline mutations. Responses were observed in patients with alterations in the DDR genes
, and
.
In this prospective, genomics-driven study of rucaparib in mCRPC, we found limited radiographic/PSA responses to PARP inhibition in men with alterations in
, or
. However, patients with alterations in other DDR-associated genes (e.g.,
) may benefit from PARP inhibition.
.
Summary Background MDV3100 is an androgen-receptor antagonist that blocks androgens from binding to the androgen receptor and prevents nuclear translocation and co-activator recruitment of the ...ligand-receptor complex. It also induces tumour cell apoptosis, and has no agonist activity. Because growth of castration-resistant prostate cancer is dependent on continued androgen-receptor signalling, we assessed the antitumour activity and safety of MDV3100 in men with this disease. Methods This phase 1–2 study was undertaken in five US centres in 140 patients. Patients with progressive, metastatic, castration-resistant prostate cancer were enrolled in dose-escalation cohorts of three to six patients and given an oral daily starting dose of MDV3100 30 mg. The final daily doses studied were 30 mg (n=3), 60 mg (27), 150 mg (28), 240 mg (29), 360 mg (28), 480 mg (22), and 600 mg (3). The primary objective was to identify the safety and tolerability profile of MDV3100 and to establish the maximum tolerated dose. The trial is registered with ClinicalTrials.gov , number NCT00510718. Findings We noted antitumour effects at all doses, including decreases in serum prostate-specific antigen of 50% or more in 78 (56%) patients, responses in soft tissue in 13 (22%) of 59 patients, stabilised bone disease in 61 (56%) of 109 patients, and conversion from unfavourable to favourable circulating tumour cell counts in 25 (49%) of the 51 patients. PET imaging of 22 patients to assess androgen-receptor blockade showed decreased18 F-fluoro-5α-dihydrotestosterone binding at doses from 60 mg to 480 mg per day (range 20–100%). The median time to progression was 47 weeks (95% CI 34–not reached) for radiological progression. The maximum tolerated dose for sustained treatment (>28 days) was 240 mg. The most common grade 3–4 adverse event was dose-dependent fatigue (16 11% patients), which generally resolved after dose reduction. Interpretation We recorded encouraging antitumour activity with MDV3100 in patients with castration-resistant prostate cancer. The results of this phase 1–2 trial validate in man preclinical studies implicating sustained androgen-receptor signalling as a driver in this disease. Funding Medivation, the Prostate Cancer Foundation, National Cancer Institute, the Howard Hughes Medical Institute, Doris Duke Charitable Foundation, and Department of Defense Prostate Cancer Clinical Trials Consortium.
There are more than 2 million prostate cancer survivors in the United States. Primary therapy with surgery or radiation results in permanent changes in sexual function. More than half of these men ...are subsequently treated with androgen deprivation therapy (ADT) at some point. The addition of ADT further compromises sexuality, intimacy, and a couple's relationship. This review will highlight the challenges faced by patients and couples and reveal the tremendous need for better education of physicians, patients, and couples as well as for more research in sexuality and intimacy with the goal of improving quality of life for this large population of survivors. Suggestions for clinicians to better help patients and their partners regarding sexuality and intimacy are offered.
Androgen deprivation therapy (ADT), a mainstay of therapy for advanced prostate cancer (CaP), may raise patients’ risk of cardiovascular disease (CVD) and related adverse events. The new androgen ...receptor (AR)-targeted agents are associated with hypertension and cardiovascular events. The most common non-CaP cause of death in men with CaP is CVD. The purpose of this review is to raise awareness of the metabolic and CV risks of ADT and to encourage proper monitoring of patients treated with hormonal agents.
To review the cardiovascular and metabolic risk profiles of hormonal agents in managing patients with advanced CaP, the author searched PubMed, meeting abstracts, and clinicaltrials.gov from 1941 through early 2020 using search terms such as locally advanced CaP guidelines, gonadotropin-releasing hormone (GnRH) agonist/antagonist, ADT, CaP, CVD, abdominal obesity metabolic syndrome, and cerebrovascular disorder. The author ultimately selected 42 of the most relevant publications for inclusion in this paper.
Data regarding cardiovascular risk in patients with CaP on ADT are inconsistent, though there may be evidence of less risk in GnRH antagonists than GnRH agonists in men with pre-existing CVD. Observational post hoc studies generally show higher risks for GnRH agonists than GnRH antagonists. A review of 6 phase 3 trials found that patients treated with GnRH antagonists had lower cardiovascular risk than those treated with agonists during the first year of ADT, and these differences were especially significant among men with pre-existing CVD. Additionally, a small prospective randomized phase 2 study, as well as a large phase 3 trial, showed that there were significantly more major adverse cardiovascular events in patients treated with a GnRH agonist compared to a GnRH antagonist. In addition, the AR-targeted agents in conjunction with ADT have been shown to have more hypertension and/or cardiovascular risk than ADT plus placebo in numerous phase 3 trials.
Whether there is a difference in CVD risk between GnRH agonists and antagonists is the subject of an ongoing phase 3 trial with cardiovascular endpoints. Addition of newer AR-targeted agents may confer additional risk over ADT alone. Clinicians treating advanced CaP should be aware of underlying comorbidities of their patients before choosing either conventional ADT or adding AR-targeted agents. Physicians should monitor patients for hypertension, diabetes, and cardiovascular side effects that may require intervention in order to minimize downstream adverse events and should communicate with other colleagues on the patient's health care team to ensure the best outcomes.
Exosomes have been proposed as vehicles for microRNA (miRNA) -based intercellular communication and a source of miRNA biomarkers in bodily fluids. Although exosome preparations contain miRNAs, a ...quantitative analysis of their abundance and stoichiometry is lacking. In the course of studying cancer-associated extracellular miRNAs in patient blood samples, we found that exosome fractions contained a small minority of the miRNA content of plasma. This low yield prompted us to perform a more quantitative assessment of the relationship between miRNAs and exosomes using a stoichiometric approach. We quantified both the number of exosomes and the number of miRNA molecules in replicate samples that were isolated from five diverse sources (i.e., plasma, seminal fluid, dendritic cells, mast cells, and ovarian cancer cells). Regardless of the source, on average, there was far less than one molecule of a given miRNA per exosome, even for the most abundant miRNAs in exosome preparations (mean ± SD across six exosome sources: 0.00825 ± 0.02 miRNA molecules/exosome). Thus, if miRNAs were distributed homogenously across the exosome population, on average, over 100 exosomes would need to be examined to observe one copy of a given abundant miRNA. This stoichiometry of miRNAs and exosomes suggests that most individual exosomes in standard preparations do not carry biologically significant numbers of miRNAs and are, therefore, individually unlikely to be functional as vehicles for miRNA-based communication. We propose revised models to reconcile the exosome-mediated, miRNA-based intercellular communication hypothesis with the observed stoichiometry of miRNAs associated with exosomes.
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.
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