Androgen receptor activity in T cells limits checkpoint blockade efficacy.

Immune checkpoint blockade has revolutionized the field of oncology, inducing durable anti-tumour immunity in solid tumours. In patients with advanced prostate cancer, immunotherapy treatments have largely failed1-5. Androgen deprivation therapy is classically administered in these patients to inhibit tumour cell growth, and we postulated that this therapy also affects tumour-associated T cells. Here we demonstrate that androgen receptor (AR) blockade sensitizes tumour-bearing hosts to effective checkpoint blockade by directly enhancing CD8 T cell function. Inhibition of AR activity in CD8 T cells prevented T cell exhaustion and improved responsiveness to PD-1 targeted therapy via increased IFNγ expression. AR bound directly to Ifng and eviction of AR with a small molecule significantly increased cytokine production in CD8 T cells. Together, our findings establish that T cell intrinsic AR activity represses IFNγ expression and represents a novel mechanism of immunotherapy resistance.

Apalutamide efficacy, safety and wellbeing in older patients with advanced prostate cancer from Phase 3 randomised clinical studies TITAN and SPARTAN.

BACKGROUND: Apalutamide plus androgen-deprivation therapy (ADT) improved outcomes in metastatic castration-sensitive prostate cancer (mCSPC) and non-metastatic castration-resistant PC (nmCRPC) in the Phase 3 randomised TITAN and SPARTAN studies, respectively, and maintained health-related quality of life (HRQoL). Apalutamide treatment effect by patient age requires assessment. METHODS: Post-hoc analysis assessed patients receiving 240 mg/day apalutamide (525 TITAN and 806 SPARTAN) or placebo (527 TITAN and 401 SPARTAN) with ongoing ADT, stratified by age groups. Prostate-specific antigen declines, radiographic progression-free survival, metastasis-free survival, overall survival (OS), HRQoL and safety were assessed using descriptive statistics, Kaplan-Meier method, Cox proportional-hazards model and mixed-effects model for repeated measures. RESULTS: Hazard ratios (95% confidence intervals) generally favoured apalutamide plus ADT versus ADT alone across all endpoints regardless of age; e.g., OS values were 0.57 (0.40-0.80), 0.70 (0.54-0.91) and 0.74 (0.40-1.39) (TITAN) and 0.39 (0.19-0.78), 0.89 (0.69-1.16) and 0.81 (0.58-1.15) (SPARTAN) in patients aged <65, 65-79 and ≥80 years. Regardless of age, apalutamide also maintained HRQoL and was tolerated well with a potential trend in rates of adverse events increasing with age. Limitations include post-hoc nature and variability in sample size of age groups. CONCLUSIONS: Apalutamide plus ADT was an effective and well-tolerated option maintaining HRQoL in patients with mCSPC and nmCRPC regardless of age. CLINICAL TRIAL REGISTRATION: TITAN (NCT02489318); SPARTAN (NCT01946204).

Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer.

BACKGROUND: Apalutamide, a competitive inhibitor of the androgen receptor, is under development for the treatment of prostate cancer. We evaluated the efficacy of apalutamide in men with nonmetastatic castration-resistant prostate cancer who were at high risk for the development of metastasis. METHODS: We conducted a double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less. Patients were randomly assigned, in a 2:1 ratio, to receive apalutamide (240 mg per day) or placebo. All the patients continued to receive androgen-deprivation therapy. The primary end point was metastasis-free survival, which was defined as the time from randomization to the first detection of distant metastasis on imaging or death. RESULTS: A total of 1207 men underwent randomization (806 to the apalutamide group and 401 to the placebo group). In the planned primary analysis, which was performed after 378 events had occurred, median metastasis-free survival was 40.5 months in the apalutamide group as compared with 16.2 months in the placebo group (hazard ratio for metastasis or death, 0.28; 95% confidence interval [CI], 0.23 to 0.35; P<0.001). Time to symptomatic progression was significantly longer with apalutamide than with placebo (hazard ratio, 0.45; 95% CI, 0.32 to 0.63; P<0.001). The rate of adverse events leading to discontinuation of the trial regimen was 10.6% in the apalutamide group and 7.0% in the placebo group. The following adverse events occurred at a higher rate with apalutamide than with placebo: rash (23.8% vs. 5.5%), hypothyroidism (8.1% vs. 2.0%), and fracture (11.7% vs. 6.5%). CONCLUSIONS: Among men with nonmetastatic castration-resistant prostate cancer, metastasis-free survival and time to symptomatic progression were significantly longer with apalutamide than with placebo. (Funded by Janssen Research and Development; SPARTAN ClinicalTrials.gov number, NCT01946204 .).

KEYNOTE-641: a Phase III study of pembrolizumab plus enzalutamide for metastatic castration-resistant prostate cancer.

Current treatment options for men with metastatic castration-resistant prostate cancer (mCRPC) are noncurative, and median survival upon development of mCRPC is approximately 3 years. The novel hormonal agent enzalutamide has an established role in the mCRPC treatment paradigm, and emerging evidence suggests potential synergism with enzalutamide and the PD-1 inhibitor pembrolizumab in men with mCRPC. Here, we describe the design and rationale for the multicenter, randomized, double-blind, Phase III KEYNOTE-641 study, which will be conducted to compare the efficacy and safety of pembrolizumab plus enzalutamide with that of enzalutamide plus placebo in mCRPC. Clinical trial registration: NCT03834493 (ClinicalTrials.gov).

The Relationship Between Checkpoint Inhibitors and the Gut Microbiome and Its Application in Prostate Cancer.

Indications for checkpoint inhibitors (CPIs) are growing rapidly within the field of oncology; however, they continue to have heterogeneous outcomes in different cancers. Other than mismatch repair deficiency, there are no consistent tests to determine a tumor's susceptibility. By exploring factors beyond the cancer cell, researchers have learned that the efficacy of CPIs may be governed by a myriad of variable host factors, including the tumor microenvironment (TME) and gut microbiome (GMB). The GMB serves as one of the primary organs of immune defense and has well-established local and systemic effects on the host immune system. Recent investigations suggest that the GMB also affects the TME. This review article discusses the concepts of a TME and a GMB and their effects on responses to CPIs. It also reviews recent research investigating these 3 topics, and how it can be applied to using CPIs in prostate cancer. By highlighting this important pathophysiologic process, we hope to provide insight into a possible explanation for differences in interindividual response to CPIs, discuss a potential method for transferring treatment efficacy between patients, and propose a method for expanding the use of CPIs to prostate cancer.

Effect of apalutamide on health-related quality of life in patients with non-metastatic castration-resistant prostate cancer: an analysis of the SPARTAN randomised, placebo-controlled, phase 3 trial.

BACKGROUND: In the SPARTAN trial, addition of apalutamide to androgen deprivation therapy, as compared with placebo plus androgen deprivation therapy, significantly improved metastasis-free survival in men with non-metastatic castration-resistant prostate cancer who were at high risk for development of metastases. We aimed to investigate the effects of apalutamide versus placebo added to androgen deprivation therapy on health-related quality of life (HRQOL). METHODS: SPARTAN is a multicentre, international, randomised, phase 3 trial. Participants were aged 18 years or older, with non-metastatic castration-resistant prostate cancer, a prostate-specific antigen doubling time of 10 months or less, and a prostate-specific antigen concentration of 2 ng/mL or more in serum. Patients were randomly assigned (2:1) to 240 mg oral apalutamide per day plus androgen deprivation therapy, or matched oral placebo plus androgen deprivation therapy, using an interactive voice randomisation system. Permuted block randomisation was used according to the three baseline stratification factors: prostate-specific antigen doubling time (>6 months vs ≤6 months), use of bone-sparing drugs (yes vs no), and presence of local-regional nodal disease (N0 vs N1). Each treatment cycle was 28 days. The primary endpoint was metastasis-free survival. The trial was unblinded in July, 2017. In this prespecified exploratory analysis we assessed HRQOL using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D-3L questionnaires, which we collected at baseline, day 1 of cycle 1 (before dose), day 1 of treatment cycles 1-6, day 1 of every two cycles from cycles 7 to 13, and day 1 of every four cycles thereafter. This study is registered with ClinicalTrials.gov, number NCT01946204. FINDINGS: Between Oct 14, 2013, and Dec 15, 2016, we randomly assigned 1207 patients to receive apalutamide (n=806) or placebo (n=401). The clinical cutoff date, as for the primary analysis, was May 19, 2017. Median follow-up for overall survival was 20·3 months (IQR 14·8-26·6). FACT-P total and subscale scores were associated with a preservation of HRQOL from baseline to cycle 29 in the apalutamide group; there were similar results for EQ-5D-3L. At baseline, the mean for FACT-P total score in both the apalutamide and placebo groups were consistent with the FACT-P general population norm for US adult men. Group mean patient-reported outcome scores over time show that HRQOL was maintained from baseline after initiation of apalutamide treatment and was similar over time among patients receiving apalutamide versus placebo. Least-squares mean change from baseline shows that HRQOL deterioration was more apparent in the placebo group. INTERPRETATION: In asymptomatic men with high-risk non-metastatic castration-resistant prostate cancer, HRQOL was maintained after initiation of apalutamide treatment. Considered with findings from SPARTAN, patients who received apalutamide had longer metastasis-free survival and longer time to symptomatic progression than did those who received placebo, while preserving HRQOL. FUNDING: Janssen Research & Development.

Gonadotropin-Releasing Hormone Antagonists in Prostate Cancer.

Androgen deprivation therapy (ADT) comes in several forms, such as surgical castration or medical castration using gonadotropin-releasing hormone (GnRH) agonist or GnRH antagonist therapy. ADT is a critical treatment for high-risk and metastatic prostate cancer. There are important differences between GnRH agonists and antagonists. Here we review the mechanism of action between GnRH agonists and antagonists and the studies that led to the approval of degarelix. We also comment on the potential risks and benefits of degarelix, particularly when it comes to cardiovascular health. Finally, we describe an oral GnRH antagonist, which is not currently used in prostate cancer, but is included for completeness.

Docetaxel and mitoxantrone before radical prostatectomy in men with high-risk prostate cancer: 10-year follow-up and immune correlates.

The aims of this study were to report the clinical outcomes in a cohort of men with high-risk prostate cancer treated with neoadjuvant docetaxel and mitoxantrone 10 years after treatment, identify pretreatment clinical parameters that may be predictors of recurrence, and describe tumor-infiltrating leukocytes present in radical prostatectomy specimens. We conducted a phase I/II study of neoadjuvant docetaxel and mitoxantrone before radical prostatectomy in high-risk localized prostate cancer to determine the feasibility of this combination and predictors of prostate cancer recurrence after cytotoxic chemotherapy. After 10 years of follow-up, 34 (63%) of 54 participants experience a recurrence. In univariate analysis, prostate-specific antigen (PSA) density (P=0.01), pathological stage (P=0.03), lymph node status (P<0.0001), seminal vesicle invasion (P=0.003), and tissue vascular endothelial growth factor (VEGF) expression (P=0.016) were significantly associated with recurrence. In multivariate analysis, only lymph node status, PSA density, and VEGF expression were significant predictors of disease recurrence. We used a tissue microarray for the first 50 participants to characterize the tumor-infiltrating lymphocytes and evaluate them for association with recurrence. We measured CD3, CD4, CD8, FoxP3, CD20, CD15, CD68, and CD163 by immunohistochemistry in both tumor and normal prostate specimens, but did not find an association between immunophenotype and recurrence. There was a significantly different density of CD68 and CD163 cells between normal and tumor tissue. Lymph node status, PSA density, and tissue VEGF expression predict recurrence after chemotherapy for high-risk prostate cancer. Additional studies are needed to determine the potential benefit of chemotherapy in the neoadjuvant setting.

Cyclooxygenase-2 (COX-2) inhibition for prostate cancer chemoprevention: double-blind randomised study of pre-prostatectomy celecoxib or placebo.

OBJECTIVE: To evaluate the biological effects of selective cyclooxygenase-2 inhibition on prostate tissue in patients undergoing radical prostatectomy (RP). PATIENTS AND METHODS: Patients with localised prostate cancer were randomised to receive either celecoxib 400 mg twice daily or placebo for 4 weeks before RP. Specimens were analysed for levels of apoptosis, prostaglandins, and androgen receptor (AR). Effects on serum prostate-specific antigen (PSA) and postoperative opioid use were also measured. RESULTS: In all, 28 of 44 anticipated patients enrolled and completed treatment. One patient in the celecoxib arm had a myocardial infarction postoperatively. For this reason, and safety concerns in other studies, enrolment was halted. The apoptosis index (AI) in tumour cells was 0.29% [95% confidence interval (CI) 0.11-0.47%] vs 0.39% (95% CI 0.00-0.84%) in the celecoxib and placebo arms, respectively (P = 0.68). The AI in benign cells was 0.18% (95% CI 0.03-0.32%) vs 0.13% (95% CI 0.00-0.28%) in the celecoxib and placebo arms, respectively (P = 0.67). Prostaglandin E2 and AR levels were similar in cancerous and benign tissues when comparing the two arms. The median baseline PSA level was 6.0 and 6.2 ng/mL for the celecoxib and placebo groups, respectively, and did not significantly change after celecoxib treatment. There was no difference in postoperative opiate usage between arms. CONCLUSION: Celecoxib had no effect on apoptosis, prostaglandins or AR levels in cancerous or benign prostate tissues. These findings coupled with drug safety concerns should serve to limit interest in these selective drugs as chemopreventive agents.

Open-label, multicenter, phase 1 study of alisertib (MLN8237), an aurora A kinase inhibitor, with docetaxel in patients with solid tumors.

BACKGROUND: This study was designed to determine the safety, tolerability, and pharmacokinetics (PK) of alisertib (MLN8237) in combination with docetaxel and to identify a recommended dose for the combination. METHODS: Adults with metastatic cancer were treated on 21-day cycles with alisertib (10, 20, 30, or 40 mg) twice daily on days 1 to 7 or days 1 to 5 and with docetaxel (75 or 60 mg/m(2) ) on day 1. The primary objectives were to assess the safety and tolerability of the combination and to determine the recommended phase 2 dose (RP2D) for future studies. Secondary objectives included an efficacy assessment and PK analyses of docetaxel and alisertib. RESULTS: Forty-one patients participated. Eight dose levels were explored with various doses of alisertib and docetaxel. The dose-limiting toxicities were neutropenic fever, neutropenia without fever, stomatitis, and urinary tract infection. The RP2D of this combination was 20 mg of alisertib twice daily on days 1 to 7 and intravenous docetaxel at 75 mg/m(2) on day 1 in 21-day cycles. Eight of the 28 patients (29%) who were efficacy-evaluable had objective responses. These included 1 complete response in a patient with bladder cancer, 6 partial responses in patients with castration-resistant prostate cancer, and 1 partial response in a patient with angiosarcoma. Concomitant administration of alisertib did not produce any clinically meaningful change in docetaxel PK. CONCLUSIONS: Alisertib at 20 mg twice daily on days 1 to 7 with intravenous docetaxel at 75 mg/m(2) on day 1 in a 21-day cycle was well tolerated, and the combination demonstrated antitumor activity. Cancer 2016;122:2524-33. © 2016 American Cancer Society.

Treatment of Nonmetastatic Castration-Resistant Prostate Cancer.

Patients with nonmetastatic castration-resistant prostate cancer (CRPC) are a heterogeneous population with regard to risk of progression to metastatic disease. Treatment selection for nonmetastatic CRPC must balance the risk of disease progression with the side effects of available therapies. Several medication classes are available for use in treating these patients, and other newer agents are under active clinical trial investigation. Here we review current therapies for nonmetastatic CRPC and discuss the recently completed and ongoing trials for this emerging disease state.

A phase II study of sulforaphane-rich broccoli sprout extracts in men with recurrent prostate cancer.

INTRODUCTION: Diets high in cruciferous vegetables are associated with lower risk of incidence of prostate cancer, including aggressive forms of this disease. Human intervention studies with cruciferous vegetable-rich diets also demonstrate modulation of gene expression in important pathways in prostate cells. PURPOSE: Sulforaphane is a constituent of these foods postulated to harbor the anti-neoplastic activity based on multiple tumor models. Our own work demonstrates that sulforaphane inhibits AR signaling in prostate cancer cells. Here, we report results from the first clinical trial of sulforaphane-rich extracts in men with prostate cancer. METHODS: We treated 20 patients who had recurrent prostate cancer with 200 µmoles/day of sulforaphane-rich extracts for a maximum period of 20 weeks and determined the proportion of patients with ≥50% PSA declines, the primary endpoint. Only one subject experienced a ≥50% PSA decline. Thus, the primary endpoint was not achieved. Seven patients experienced smaller PSA declines (<50%). There was also a significant lengthening of the on-treatment PSA doubling time (PSADT) compared with the pre-treatment PSADT [6.1 months pre-treatment vs. 9.6 months on-treatment (p = 0.044)]. Finally, treatment with sulforaphane-rich extracts was safe with no Grade 3 adverse events. CONCLUSIONS: Treatment with 200 µmoles/day of sulforaphane-rich extracts did not lead to ≥50% PSA declines in the majority of patients. However, because of the safety of treatment and the effects on PSADT modulation, further studies, including those with higher doses, may be warranted to clarify the role of sulforaphane as a prevention agent or treatment agent.

Interventions that may reduce depressive symptoms among prostate cancer patients: a systematic review and meta-analysis.

OBJECTIVE: Prostate cancer patients are at increased risk of depression yet there is no standard intervention to address this. The purpose of this meta-analysis is to examine the efficacy of interventions in reducing depressive symptoms in men with prostate cancer. METHODS: Searches for studies were conducted in four databases and by hand. Randomized controlled trials of any intervention relative to control for depression in prostate cancer patients at any stage of their cancer treatment were included. RESULTS: We identified 11 studies that randomized men with prostate cancer to either an intervention meant to improve some aspect of quality of life or control and reported depressive symptoms scores before and after the intervention or control condition. Two of these were not used in our meta-analysis either for concerns about quality or for lack of depression scores. The interventions identified in the remaining nine articles were exercise (four), information (three), psychotherapy or peer support (three), massage therapy (one), and medication (one). Several publications included more than one type of intervention. A meta-analysis of all studies showed that an intervention of some types significantly improved depressive symptom scores relative to the control condition (improvement in depression score by -0.86 unit (95% CI: -1.42, -0.31)). Isolating the peer support/psychotherapy studies also showed significant improvement (improvement in depression score by -1.09 unit (95% CI: -2.05, -0.13)). CONCLUSION: Treatments to improve depressive symptoms in men with prostate cancer may be effective, with the best evidence supporting the use of peer support/psychotherapy.

Reducing Skeletal-Related Events in Metastatic Castration-Resistant Prostate Cancer.

Skeletal-related events contribute substantially to morbidity, mortality and cost in men with metastatic castration-resistant prostate cancer (mCRPC). There are five agents available for treatment in mCRPC that reduce skeletal-related events. Here we discuss the efficacy and safety of zoledronic acid, denosumab, enzalutamide, abiraterone, and radium-223. We include data on and a discussion of duration of treatment with zoledronic acid and denosumab, the only two of these agents that do not have a clinically proven anticancer effect. Finally, we review the available data regarding the cost of denosumab compared with that of zoledronic acid.

Androgen receptor activity inversely correlates with immune cell infiltration and immunotherapy response across multiple cancer lineages.

There is now increasing recognition of the important role of androgen receptor (AR) in modulating immune function. To gain a comprehensive understanding of the effects of AR activity on cancer immunity, we employed a computational approach to profile AR activity in 33 human tumor types using RNA-Seq datasets from The Cancer Genome Atlas. Our pan-cancer analysis revealed that the genes most negatively correlated with AR activity across cancers are involved in active immune system processes. Importantly, we observed a significant negative correlation between AR activity and IFNγ pathway activity at the pan-cancer level. Indeed, using a matched biopsy dataset from subjects with prostate cancer before and after AR-targeted treatment, we verified that inhibiting AR enriches immune cell abundances and is associated with higher IFNγ pathway activity. Furthermore, by analyzing immunotherapy datasets in multiple cancers, our results demonstrate that low AR activity was significantly associated with a favorable response to immunotherapy. Together, our data provide a comprehensive assessment of the relationship between AR signaling and tumor immunity.

Metastatic Hormone-Sensitive Prostate Cancer: Toward an Era of Adaptive and Personalized Treatment.

The advent of more effective treatment combinations for metastatic hormone-sensitive prostate cancer (mHSPC) has been built on successes in therapy development for metastatic, castration-resistant prostate cancer (mCRPC). Both disease phases hold similar challenges and questions. Is there an optimal therapy sequence to maximize disease control and balance treatment burden? Are there clinical and biologically based subgroups that inform personalized and/or adaptive strategies? How can clinicians interpret data from clinical trials in the context of rapidly evolving technologies? Herein, we review the contemporary landscape of treatment for mHSPC, including disease subgroups informing both intensification and potential deintensification strategies. Furthermore, we provide current insights into the complex biology of mHSPC and discuss the potential clinical application of biomarkers to guide therapy selection and the development of novel personalized approaches.

Evolution of structural rearrangements in prostate cancer intracranial metastases.

Intracranial metastases in prostate cancer are uncommon but clinically aggressive. A detailed molecular characterization of prostate cancer intracranial metastases would improve our understanding of their pathogenesis and the search for new treatment strategies. We evaluated the clinical and molecular characteristics of 36 patients with metastatic prostate cancer to either the dura or brain parenchyma. We performed whole genome sequencing (WGS) of 10 intracranial prostate cancer metastases, as well as WGS of primary prostate tumors from men who later developed metastatic disease (n = 6) and nonbrain prostate cancer metastases (n = 36). This first whole genome sequencing study of prostate intracranial metastases led to several new insights. First, there was a higher diversity of complex structural alterations in prostate cancer intracranial metastases compared to primary tumor tissues. Chromothripsis and chromoplexy events seemed to dominate, yet there were few enrichments of specific categories of structural variants compared with non-brain metastases. Second, aberrations involving the AR gene, including AR enhancer gain were observed in 7/10 (70%) of intracranial metastases, as well as recurrent loss of function aberrations involving TP53 in 8/10 (80%), RB1 in 2/10 (20%), BRCA2 in 2/10 (20%), and activation of the PI3K/AKT/PTEN pathway in 8/10 (80%). These alterations were frequently present in tumor tissues from other sites of disease obtained concurrently or sequentially from the same individuals. Third, clonality analysis points to genomic factors and evolutionary bottlenecks that contribute to metastatic spread in patients with prostate cancer. These results describe the aggressive molecular features underlying intracranial metastasis that may inform future diagnostic and treatment approaches.

Gender and Patient Satisfaction in a Veterans Health Administration Outpatient Chemotherapy Unit.

Background: Our objective was to explore whether differences in patient satisfaction based on gender exist at the Veterans Affairs Portland Health Care System (VAPHCS) outpatient chemotherapy infusion unit. Methods: Veterans who received outpatient infusion treatments at the VAPHCS outpatient chemotherapy infusion unit from 2018 to 2020 were invited to take an anonymous survey. Response differences were analyzed using Fisher exact and Welch t tests. Male and female patient lists were first generated based on Computerized Patient Record System designation, then defined and results reported based on gender self-identification from survey responses. Results: The survey was conducted over a 2-week period during January and February of 2021. In total, 69 veterans were contacted: 21 (70%) of 30 female and 20 (51%) of 39 male veterans completed the survey. Most (62%) female patients were aged < 65 years, and 52% were treated for breast cancer. Most (90%) male patients were aged ≥ 65 years, and most commonly treated for prostate cancer (20%) or a hematologic malignancy (20%). Using our survey, patient satisfaction (SD) was 8.7 (2.2) on a 10-point scale among women, and 9.6 (0.6) among men (P = .11). History of sexual abuse or harassment was reported by 86% of women compared with 10% of men (P < .001). Women reported feeling uncomfortable around other patients in the infusion unit compared with men (29% vs 0%; P = .02) and discomfort in relaying uncomfortable feelings to a clinician (29% vs 0%; P = .02). Conclusions: Gender seems to be related to how veterans with cancer perceive their ambulatory cancer care. This may be due to the combination of a high history of sexual abuse and/or harassment among women who represent a minority of the total infusion unit population, the majority of whom receive treatment for a primarily gender-specific breast malignancy. Analysis was limited by the small sample size of women, many with advanced malignancy.

Deep Prostate-specific Antigen Response following Addition of Apalutamide to Ongoing Androgen Deprivation Therapy and Long-term Clinical Benefit in SPARTAN.

BACKGROUND: Apalutamide plus androgen deprivation therapy (ADT) significantly improved metastasis-free survival (MFS), overall survival (OS), and time to prostate-specific antigen (PSA) progression in the placebo-controlled SPARTAN study of high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC). OBJECTIVE: To assess the relationships between PSA kinetics, outcomes, and molecular subtypes in SPARTAN. DESIGN, SETTING, AND PARTICIPANTS: The authors conducted a post hoc analysis of nmCRPC patients randomized to receive apalutamide (n = 806) or placebo (n = 401) plus ADT and a subset stratified by molecular classifiers. INTERVENTION: Apalutamide 240 mg/d. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The association between PSA kinetics and MFS, OS, time to PSA progression, and molecular subtypes was evaluated using the landmark analysis and Kaplan-Meier methods. RESULTS AND LIMITATIONS: By 3 mo, PSA decreased in most apalutamide-treated patients and increased in most placebo-treated patients. After apalutamide, the median time to PSA nadir, confirmed ≥50% PSA reduction, ≥90% PSA reduction, and PSA ≤0.2 ng/ml were 7.4, 1.0, 1.9, and 2.8 mo, respectively. By 6 mo, 90%, 57%, and 32% of apalutamide patients had ≥50% PSA reduction, ≥90% PSA reduction, and PSA ≤0.2 ng/ml, respectively, while only 1.5% of placebo patients experienced ≥50% PSA reduction. PSA reductions were observed within 3 mo and up to 12 mo of apalutamide treatment, and were similar across molecular subtypes. Deep PSA responses (≥90% PSA reduction or PSA ≤0.2 ng/ml) at landmark 6-mo apalutamide treatment were significantly associated with improved time to PSA progression (hazard ratio {HR} [95% confidence interval {CI}] 0.25 [0.18-0.33] or 0.13 [0.08-0.21]), MFS (0.41 [0.29-0.57] or 0.3 [0.19-0.47]), and OS (0.45 [0.35-0.59] or 0.26 [0.18-0.38]; p < 0.001 for all). CONCLUSIONS: Apalutamide plus ADT produced rapid, deep, and durable PSA responses by 6-mo treatment regardless of assessed molecular prognostic markers. An early PSA response with apalutamide was associated with clinical benefits, supporting prognostic value of PSA monitoring. PATIENT SUMMARY: In this report, we describe how prostate-specific antigen (PSA) levels relate to outcomes in patients with nonmetastatic castration-resistant prostate cancer treated with apalutamide plus androgen deprivation therapy (ADT). We found that treatment with apalutamide plus ADT resulted in rapid, deep, and durable PSA responses in the majority of patients, including those with high-risk molecular subtypes, which were associated with improved survival.

Composition of gastrointestinal microbiota in association with treatment response in individuals with metastatic castrate resistant prostate cancer progressing on enzalutamide and initiating treatment with anti-PD-1 (pembrolizumab).

Recent studies in cancer patients and animal models demonstrate that intestinal microbiota influence the therapeutic efficacy of cancer treatments, including immune checkpoint inhibition. However, no studies to-date have investigated relationships between gastrointestinal microbiota composition and response to checkpoint inhibition in advanced metastatic castrate resistant prostate cancer (mCRPC). We performed 16S rRNA gene sequencing of fecal DNA from 23 individuals with mCRPC progressing on enzalutamide and just prior to treatment with anti-PD-1 (pembrolizumab) to determine whether certain features of the microbiome are associated with treatment response (defined as serum PSA decrease >50% at any time on treatment or radiographic response per RECIST V.1.1). Global bacterial composition was similar between responders and non-responders, as assessed by multiple alpha and beta diversity metrics. However, certain bacterial taxa identified by sequencing across multiple 16S rRNA hypervariable regions were consistently associated with response, including the archetypal oral bacterium Streptococcus salivarius. Quantitative PCR (qPCR) of DNA extracts from fecal samples confirmed increased Streptococcus salivarius fecal levels in responders, whereas qPCR of oral swish DNA extracts showed no relationship between oral Streptococcus salivarius levels and response status. Contrary to previous reports in other cancer types, Akkermansia muciniphila levels were reduced in responder samples as assessed by both 16S rRNA sequencing and qPCR. We further analyzed our data in the context of a previously published "integrated index" describing bacteria associated with response and non-response to checkpoint inhibition. We found that the index was not reflective of response status in our cohort. Lastly, we demonstrate little change in the microbiome over time, and with pembrolizumab treatment. Our results suggest that the association between fecal microbiota and treatment response to immunotherapy may be unique to cancer type and/or previous treatment history.