Germline biomarkers predict toxicity to anti-PD1/PDL1 checkpoint therapy.

BACKGROUND: There is great interest in finding ways to identify patients who will develop toxicity to cancer therapies. This has become especially pressing in the era of immune therapy, where toxicity can be long-lasting and life-altering, and primarily comes in the form of immune-related adverse effects (irAEs). Treatment with the first drugs in this class, anti-programmed death 1 (anti-PD1)/programmed death-ligand 1 (PDL1) checkpoint therapies, results in grade 2 or higher irAEs in up to 25%-30% of patients, which occur most commonly within the first 6 months of treatment and can include arthralgias, rash, pruritus, pneumonitis, diarrhea and/or colitis, hepatitis, and endocrinopathies. We tested the hypothesis that germline microRNA pathway functional variants, known to predict altered systemic stress responses to cancer therapies, would predict irAEs in patients across cancer types. METHODS: MicroRNA pathway variants were evaluated for an association with grade 2 or higher toxicity using four classifiers on 62 patients with melanoma, and then the panel's performance was validated on 99 patients with other cancer types. Trained classifiers included classification trees, LASSO-regularized logistic regression, boosted trees, and random forests. Final performance measures were reported on the training set using leave-one-out cross validation and validated on held-out samples. The predicted probability of toxicity was evaluated for its association, if any, with response categories to anti-PD1/PDL1 therapy in the melanoma cohort. RESULTS: A biomarker panel was identified that predicts toxicity with 80% accuracy (F1=0.76, area under the curve (AUC)=0.82) in the melanoma training cohort and 77.6% accuracy (F1=0.621, AUC=0.778) in the pan-cancer validation cohort. In the melanoma cohort, the predictive probability of toxicity was not associated with response categories to anti-PD1/PDL1 therapy (p=0.70). In the same cohort, the most significant biomarker of toxicity in RAC1, predicting a greater than ninefold increased risk of toxicity (p<0.001), was also not associated with response to anti-PD1/PDL1 therapy (p=0.151). CONCLUSIONS: A germline microRNA-based biomarker signature predicts grade 2 and higher irAEs to anti-PD1/PDL1 therapy, regardless of tumor type, in a pan-cancer manner. These findings represent an important step toward personalizing checkpoint therapy, the use of which is growing rapidly.

Phase Ib study of patients with metastatic castrate-resistant prostate cancer treated with different sequencing regimens of atezolizumab and sipuleucel-T.

BACKGROUND: Combining an immune checkpoint inhibitor with a tumor vaccine may modulate the immune system to leverage complementary mechanisms of action that lead to sustained T-cell activation and a potent prolonged immunotherapeutic response in metastatic castration resistant prostate cancer (mCRPC). METHODS: Subjects with asymptomatic or minimally symptomatic mCRPC were randomly assigned in a 1:1 ratio to receive either atezolizumab followed by sipuleucel-T (Arm 1) or sipuleucel-T followed by atezolizumab (Arm 2). The primary endpoint was safety, while secondary endpoints included preliminary clinical activity such as objective tumor response and systemic immune responses that could identify key molecular and immunological changes associated with sequential administration of atezolizumab and sipuleucel-T. RESULTS: A total of 37 subjects were enrolled. The median age was 75.0 years, median prostate specific antigen (PSA) was 21.9 ng/mL, and subjects had a median number of three prior treatments. Most subjects (83.8%) had at least one treatment-related adverse event. There were no grade 4 or 5 toxicities attributed to either study drug. Immune-related adverse events and infusion reactions occurred in 13.5% of subjects, and all of which were grade 1 or 2. Of 23 subjects with Response Evaluation Criteria in Solid Tumors measurable disease, only one subject in Arm 2 had a partial response (PR) and four subjects overall had stable disease (SD) at 6 months reflecting an objective response rate of 4.3% and a disease control rate of 21.7%. T-cell receptor diversity was higher in subjects with a response, including SD. Immune response to three novel putative antigens (SIK3, KDM1A/LSD1, and PIK3R6) appeared to increase with treatment. CONCLUSIONS: Overall, regardless of the order in which they were administered, the combination of atezolizumab with sipuleucel-T appears to be safe and well tolerated with a comparable safety profile to each agent administered as monotherapy. Correlative immune studies may suggest the combination to be beneficial; however, further studies are needed. TRIAL REGISTRATION NUMBER: NCT03024216.

Real World Experience With Pembrolizumab in Recurrent or Advanced Prostate Cancer.

INTRODUCTION: Phase II trials have shown activity with pembrolizumab against prostate cancer. However, the clinical factors predictive of a response to pembrolizumab in men with prostate cancer are unknown. PATIENTS AND METHODS: A total of 54 consecutive men with progressive, recurrent, or advanced prostate cancer were treated with 1 to 12 cycles of pembrolizumab 200 mg every 3 weeks with or without stereotactic body radiotherapy (SBRT). RESULTS: For the 31 men evaluable for response, the median age, prostate-specific antigen (PSA) level, and Gleason score were 75 years, 30 ng/mL, and 8 (4 + 4), respectively, which were similar to those for the 23 nonevaluable patients. The treatments received before pembrolizumab were enzalutamide in 26, abiraterone in 18, and sipuleucel-T in 23. All but 4 men had had castrate-resistant disease. Of the 54 men, 31 had completed ≥ 4 cycles of pembrolizumab and were evaluable for the response. Ten men had undergone SBRT to an isolated metastasis shortly before or during pembrolizumab treatment, with the goal of inducing an abscopal effect. The clinical characteristics of the 17 men with a response or stable disease were compared with those of the 14 men with progressive disease. Grade ≥ 2 toxicity occurred in 16 men (30%). PSA stabilization or a response occurred in slightly more than one half (55%) of the men treated with ≥ 4 cycles of pembrolizumab. Five patients had a notable PSA decline of > 50%, which were sustained as long as they had continued receiving pembrolizumab. A PSA response or stabilization was more common for men who had begun taking pembrolizumab with a lower PSA level, fewer bone metastases, and fewer mutations and without previous chemotherapy. A statistically nonsignificant trend toward stabilization or a response was observed in men who had undergone concomitant SBRT. CONCLUSION: Pembrolizumab showed modest anticancer activity against metastatic castrate-resistant prostate cancer. A PSA response or stabilization occurred more frequently in men with less-advanced disease.

Real-world outcomes of sipuleucel-T treatment in PROCEED, a prospective registry of men with metastatic castration-resistant prostate cancer.

BACKGROUND: The large registry, PROVENGE Registry for the Observation, Collection, and Evaluation of Experience Data (PROCEED)(NCT01306890), evaluated sipuleucel-T immunotherapy for asymptomatic/minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). METHODS: PROCEED enrolled patients with mCRPC receiving 3 biweekly sipuleucel-T infusions. Assessments included overall survival (OS), serious adverse events (SAEs), cerebrovascular events (CVEs), and anticancer interventions (ACIs). Follow-up was for ≥3 years or until death or study withdrawal. RESULTS: In 2011-2017, 1976 patients were followed for 46.6 months (median). The median age was 72 years, and the baseline median prostate-specific antigen level was 15.0 ng/mL; 86.7% were white, and 11.6% were African American. Among the patients, 1902 had 1 or more sipuleucel-T infusions. The median OS was 30.7 months (95% confidence interval [CI], 28.6-32.2 months). Known prognostic factors were independently associated with OS in a multivariable analysis. Among the 1255 patients who died, 964 (76.8%) died of prostate cancer (PC) progression. The median time from the first infusion to PC death was 42.7 months (95% CI, 39.4-46.2 months). The incidence of sipuleucel-T-related SAEs was 3.9%. The incidence of CVEs was 2.8%, and the rate per 100 person-years was 1.2 (95% CI, 0.9-1.6). The CVE incidence among 11,972 patients with mCRPC from the Surveillance, Epidemiology, and End Results-Medicare database was 2.8%; the rate per 100 person-years was 1.5 (95% CI, 1.4-1.7). One or more ACIs (abiraterone, enzalutamide, docetaxel, cabazitaxel, or radium 223) were received by 77.1% of the patients after sipuleucel-T; 32.5% and 17.4% of the patients experienced 1- and 2-year treatment-free intervals, respectively. CONCLUSIONS: PROCEED provides contemporary survival data for sipuleucel-T-treated men in a real-world setting of new life-prolonging agents, which will be useful in discussing treatment options with patients and in powering future trials with sipuleucel-T. The safety and tolerability of sipuleucel-T in PROCEED were consistent with previous findings.

Cabozantinib Versus Mitoxantrone-prednisone in Symptomatic Metastatic Castration-resistant Prostate Cancer: A Randomized Phase 3 Trial with a Primary Pain Endpoint.

BACKGROUND: Bone metastases in patients with metastatic castration-resistant prostate cancer (mCRPC) are associated with debilitating pain and functional compromise. OBJECTIVE: To compare pain palliation as the primary endpoint for cabozantinib versus mitoxantrone-prednisone in men with mCRPC and symptomatic bone metastases using patient-reported outcome measures. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind phase 3 trial (COMET-2; NCT01522443) in men with mCRPC and narcotic-dependent pain from bone metastases who had progressed after treatment with docetaxel and either abiraterone or enzalutamide. INTERVENTION: Cabozantinib 60mg once daily orally versus mitoxantrone 12mg/m2 every 3wk plus prednisone 5mg twice daily orally. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was pain response at week 6 confirmed at week 12 (≥30% decrease from baseline in patient-reported average daily worst pain score via the Brief Pain Inventory without increased narcotic use). The planned sample size was 246 to achieve ≥90% power. RESULTS AND LIMITATIONS: Enrollment was terminated early because cabozantinib did not demonstrate a survival benefit in the companion COMET-1 trial. At study closure, 119 participants were randomized (cabozantinib: N=61; mitoxantrone-prednisone: N=58). Complete pain and narcotic use data were available at baseline, week 6, and week 12 for 73/106 (69%) patients. There was no significant difference in the pain response with cabozantinib versus mitoxantrone-prednisone: the proportions of responders were 15% versus 17%, a -2% difference (95% confidence interval: -16% to 11%, p=0.8). Barriers to accrual included pretreatment requirements for a washout period of prior anticancer therapy and a narcotic optimization period to maximize analgesic dosing. CONCLUSIONS: Cabozantinib treatment did not demonstrate better pain palliation than mitoxantrone-prednisone in heavily pretreated patients with mCRPC and symptomatic bone metastases. Future pain-palliation trials should incorporate briefer timelines from enrollment to treatment initiation. PATIENT SUMMARY: Cabozantinib was not better than mitoxantrone-prednisone for pain relief in patients with castration-resistant prostate cancer and debilitating pain from bone metastases.

Phase I clinical trial of sipuleucel-T combined with escalating doses of ipilimumab in progressive metastatic castrate-resistant prostate cancer.

BACKGROUND: Sipuleucel-T (SIP-T), which functions by stimulating cancer-specific dendritic cells, prolongs survival in men with prostate cancer. Ipilimumab (IPI) achieved a borderline survival advantage in a large randomized trial. SIP-T and IPI are potentially synergistic. PATIENTS AND METHODS: Nine men with progressive metastatic castrate-resistant prostate cancer (mCRPC) were treated prospectively with SIP-T followed immediately by IPI with one of the following doses of IPI: 1 mg/kg at 1 week after SIP-T; 1 mg/kg at 1 and 4 weeks after SIP-T; or 1 mg/kg at 1, 4, and 7 weeks after SIP-T. Three patients were evaluated at each level. Cancer-specific immunoglobulins directed at granulocyte-macrophage-colony-stimulating factor/prostatic acid phosphatase (PAP) fusion protein (PA2024) and PAP were measured prior to SIP-T, after SIP-T, 1 week after IPI, every other month for 5 months, then every 3 months for an additional 12 months. RESULTS: Adverse events of SIP-T were consistent with previous reports. IPI only caused a transient grade 1 rash in one patient. Median age, Gleason score, and number of previous hormonal interventions were 77 years, 8, and 3, respectively. Eight men had bone metastases and one had lymph node metastasis. Statistically significant increases in serum immunoglobulin G (IgG) and IgG-IgM specific for PA2024 and PAP occurred after SIP-T. An additional statistically significant increase in the aforementioned immunoglobulins - above the levels achieved by SIP-T - occurred after IPI. Median clinical follow-up was 36 months (range: 26-40). Three patients died from progressive disease after 9, 18, and 20 months. Out of the remaining six patients, five of them needed further treatment that included abiraterone acetate, enzalutamide, radium-223 dichloride, and spot radiation. One patient had an undetectable PSA, who did not receive any other treatment except spot radiation. Median PSA at last follow-up for the surviving patients was 3.8 (range: 0.6-7.47). CONCLUSION: In this small trial, the addition of IPI to SIP-T was well tolerated. IPI increased immunoglobulins specific for the PA2024 protein and PAP above the level achieved with SIP-T alone.

Performance characteristics and relationship of PSA value/kinetics on carbon-11 acetate PET/CT imaging in biochemical relapse of prostate cancer.

An elevated serum prostate-specific antigen (PSA) level alone cannot distinguish between local-regional recurrences and distant metastases after treatment with curative intent. With available salvage treatments, it has become important to localize the site of recurrence. 11C-Acetate PET/CT was performed in patients with rising PSA, with statistical analysis of detection rates, sites/location of detection, PSA kinetics and comparison with other tracers (FDG and Choline). Correlation to biopsy, subsequent imaging and PSA response to focal treatment was also performed. 88% (637) of 721 11C-Acetate PET/CT scans performed were positive. There was a statistically significant difference in PSA values between the positive and negative scans (P < 0.001 for mean difference) with the percentage of positive scans and PSA having a positive correlation. A PSA of 1.09 ng/mL was found to be an optimal cutoff. PSAdT was significantly correlated with a positive scan only when the PSA was < 1.0 ng/mL. For this subgroup, a PSAdT of < 3.8 months appeared significant (P < 0.05) as an optimal cutoff point. 11C-Acetate PET/CT demonstrates a high detection rate for the site of recurrence/metastasis in biochemical relapsed prostate cancer (88% overall detection rate, PPV 90.8%). This analysis suggests an optimal PSA threshold of > 1.09 ng/mL or a PSAdT of < 3.8 months when the PSA is below 1.0 ng/mL as independent predictors of positive findings.

Safety of enzalutamide in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel: expanded access in North America.

BACKGROUND: The open-label, single-arm enzalutamide expanded access program (EAP) in the United States and Canada evaluated the safety of enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) who had previously received docetaxel. METHODS: Patients (n = 507) received enzalutamide 160 mg/day until disease progression, intolerable adverse events (AEs), or commercial availability occurred. AEs and other safety variables were assessed on day 1, weeks 4 and 12, and every 12 weeks thereafter. Data following transition to commercial drug were not collected. RESULTS: Median age was 71 years (range 43-97); 426 patients (83.9%) had a baseline ECOG score of ≤1. In addition to docetaxel, the majority of patients had received prior prostate cancer treatments such as abiraterone (76.1%) or cabazitaxel (28.6%). Median study treatment duration was 2.6 months (range 0.03-9.07). The most frequently reported reasons for discontinuation were commercial availability of enzalutamide (46.7%) and progressive disease (33.7%). A total of 88.2% of patients experienced AEs; 45.4% experienced AEs with a maximum grade of 1 or 2. Fatigue (39.1%), nausea (22.7%), and anorexia (14.8%) were the most commonly reported AEs. Seizure was reported in four patients (0.8%). The most commonly reported event leading to death was progression of metastatic prostate cancer (7.7%). CONCLUSION: In this heavily pretreated EAP population with progressive mCRPC, enzalutamide was well tolerated and the safety profile was consistent with that of the AFFIRM trial.

Short-term enzalutamide treatment for the potential remission of active surveillance or intermediate-risk prostate cancer: a case study, review, and the need for a clinical trial.

Active surveillance (AS) is a widely recognized and utilized option by which prostate cancer patients with less aggressive tumors on diagnosis defer immediate traditional conventional therapy (surgery, radiation) and undergo close monitoring by a physician for any clinical or pathologic changes. The juxtaposition of low- to intermediate-risk elderly patients between effective and conventional treatment with associated risks and monitoring without the opportunity for relief of anxiety and other psychological problems can be significant. Minimal and safe treatment over 6 months with the hope of eliminating the existing disease is of significant interest to prostate cancer patients. Unfortunately, dietary supplements have failed to improve and have sometimes even contributed to disease progression. In addition, the use of multiple medications is not always appropriate or safe. In this case study, we administered low doses of enzalutamide (80 mg/day-120 mg/day) in an AS patient during a 6 month period. Results showed a significant reduction in tumor size, as evidenced by magnetic resonance imaging and color Doppler, as well as a an undetectable level of prostate specific antigen during, and immediately following treatment. The use of an oral second-generation androgen-receptor signaling inhibitor was shown to be of benefit to patients unwilling to pursue AS and conventional treatment. Administration of enzalutamide did not reduce testosterone levels, but helped maintain good quality of life, was more cost effective at low doses, and was previously shown to be heart healthy and efficacious during early stages of castration-resistant prostate cancer. Although we do not advocate enzalutamide as a treatment approach in these situations, we believe that a clinical trial to evaluate short-term low-dose treatment using enzalutamide is warranted.

Cell cycle progression score and treatment decisions in prostate cancer: results from an ongoing registry.

OBJECTIVE: The cell cycle progression (CCP) test (Prolaris) is a novel prognostic assay that provides accurate risk of prostate cancer-specific disease progression and disease specific mortality when combined with standard clinicopathologic parameters. This prospective study evaluated the impact of the CCP report on physician treatment recommendations for prostate cancer. METHODS: Physicians ordering the CCP test in clinical practice completed surveys regarding treatment recommendations before and after they received and discussed the test results with patients. Clinicians also rated the influence of the test result on treatment decisions. Treatment selections were confirmed via third-party audit of patient charts following final survey responses. RESULTS: Overall, 65% of cases showed a change between intended treatment pre- and post-CCP test reporting. Pre-CCP testing, 164 of 305 cases received a recommendation for interventional treatment. Post-CCP test, interventional therapy was recommended for 103 of these cases, a reduction of 37.2%. Conversely, 141 of 305 cases were recommended pre-CCP testing for non-interventional treatment; 108 of these remained with non-interventional treatment while 33 shifted to interventional options, a 23.4% increase. There was a 49.5% reduction in surgical interventions and a 29.6% reduction in radiation treatment. A third-party audit identified 80.2% concordance between the post-CCP testing treatment recommendation and actual treatment. Re-assignment to intervention or non-intervention generally correlated with the result of the CCP report. Study limitations included physician selection of patients for testing, no evaluation of patient input in therapeutic choice, and other potential treatment decision factors not queried by the survey. CONCLUSION: Based on responses of ordering physicians, the CCP report adds meaningful new information to risk assessment for localized prostate cancer patients. Test results led to changes in treatment with reductions and increases in interventional treatment that were directionally aligned with prostate cancer risk specified by the test.

Primary androgen deprivation (AD) followed by active surveillance (AS) for newly diagnosed prostate cancer (PC): A retrospective study.

BACKGROUND: Active surveillance (AS) is only recommended for Low-Risk prostate cancer (PC) with <34% biopsies positive. Studies describing the long-term outcome of men treated with androgen deprivation (AD) followed by AS are sparse. MATERIALS AND METHODS: One hundred two men were treated with 12 months of AD in a medical oncology clinic specializing in PC between 1998 and 2007 and were followed for a median of 7.25 years. The biopsy complete response rate after AD and the incidence of disease progression while on subsequent AS was assessed. Baseline age, D'Amico risk category, PSA velocity, percentage core biopsies, and prostate volume were evaluated as potential predictors of disease progression. RESULTS: D'Amico risk category for the 102 men: Low: n = 22, Intermediate: n = 30, and High: n = 50. Medians: Age 67.3, PSA 7.8, Gleason 3 + 4, >50% core biopsies positive, stage T1c. Seventy men had a clear biopsy and 31 of these had disease progression leading to additional treatment after a median of 52 months. D'Amico risk category of the 57 men with a positive biopsy after AD or disease progression on AS was: Low: n = 4 (18%), Intermediate: n = 16 (53%), and High: n = 37 (74%). No PC deaths occurred. Three men had clinical progression. In stepwise logistic regression analysis only higher D'Amico risk category and lower prostate volume predicted disease progression. CONCLUSIONS: Despite a high prevalence of ≥50% core biopsies positive at baseline, AD induces durable remissions in most men with Low-Risk and about half with Intermediate-Risk PC.

Comparative analysis of prostate-specific antigen free survival outcomes for patients with low, intermediate and high risk prostate cancer treatment by radical therapy. Results from the Prostate Cancer Results Study Group.

What's known on the subject? and What does the study add? Very few comparative studies to date evaluate the results of treatment options for prostate cancer using the most sensitive measurement tools. PSA has been identified as the most sensitive tool for measuring treatment effectiveness. To date, comprehensive unbiased reviews of all the current literature are limited for prostate cancer. This is the first large scale comprehensive review of the literature comparing risk stratified patients by treatment option and with long-term follow-up. The results of the studies are weighted, respecting the impact of larger studies on overall results. The study identified a lack of uniformity in reporting results amongst institutions and centres. A large number of studies have been conducted on the primary therapy of prostate cancer but very few randomized controlled trials have been conducted. The comparison of outcomes from individual studies involving surgery (radical prostatectomy or robotic radical prostatectomy), external beam radiation (EBRT) (conformal, intensity modulated radiotherapy, protons), brachytherapy, cryotherapy or high intensity focused ultrasound remains problematic due to the non-uniformity of reporting results and the use of varied disease outcome endpoints. Technical advances in these treatments have also made long-term comparisons difficult. The Prostate Cancer Results Study Group was formed to evaluate the comparative effectiveness of prostate cancer treatments. This international group conducted a comprehensive literature review to identify all studies involving treatment of localized prostate cancer published during 2000-2010. Over 18,000 papers were identified and a further selection was made based on the following key criteria: minimum/median follow-up of 5 years; stratification into low-, intermediate- and high-risk groups; clinical and pathological staging; accepted standard definitions for prostate-specific antigen failure; minimum patient number of 100 in each risk group (50 for high-risk group). A statistical analysis (standard deviational ellipse) of the study outcomes suggested that, in terms of biochemical-free progression, brachytherapy provides superior outcome in patients with low-risk disease. For intermediate-risk disease, the combination of EBRT and brachytherapy appears equivalent to brachytherapy alone. For high-risk patients, combination therapies involving EBRT and brachytherapy plus or minus androgen deprivation therapy appear superior to more localized treatments such as seed implant alone, surgery alone or EBRT. It is anticipated that the study will assist physicians and patients in selecting treatment for men with newly diagnosed prostate cancer.

Primary intermittent androgen deprivation as initial therapy for men with newly diagnosed prostate cancer.

BACKGROUND: The purpose of this study was to describe the long-term incidence of cancer progression and mortality in men with localized prostate cancer treated with primary androgen deprivation (AD). METHODS: A retrospective chart review, from a medical oncology practice specializing in prostate cancer, was conducted of 73 men eligible for surgery or radiation treated with induction AD. Entry criteria consisted of a minimum of 9 months of induction AD, treatment initiation before 1999, clinical stage < T3, and outcome defined as the incidence of delayed local therapy, cancer progression, cancer mortality, and mortality from other causes. RESULTS: Median follow-up was 12 years. Fifteen men were at low risk, 38 were at intermediate risk, and 20 were at high risk. Three men (4%) experienced metastatic disease and died of prostate cancer after 3.5, 7.7, and 11 years, respectively. Two men were in the intermediate-risk category and 1 was high risk. Nineteen men (26%) died of non-prostate cancer causes. None had metastatic disease at the time of death. Of the remaining 51 survivors, none has experienced bone metastasis. Twenty-one men (29%) required no further therapy after the first induction course of AD. Twenty-four men (33%) maintained a prostate-specific antigen (PSA) level < 5.0 ng/mL with 2 to 5 cycles of intermittent AD. Twenty-eight men (38%) underwent delayed local therapy after a median of 5.5 years. Median follow-up after local therapy was 6.2 years. Three of these men experienced subsequent rising PSA levels but none has progressed to bone metastasis. Sixteen of 20 men (80%) in the high-risk category but only 12 of 53 men (23%) in the low- and intermediate-risk categories had delayed local therapy. CONCLUSIONS: Primary intermittent AD is feasible for men with localized prostate cancer. Men who are younger and men with high-risk disease undergo delayed local therapy more frequently.

Abiraterone and increased survival in metastatic prostate cancer.

BACKGROUND: Biosynthesis of extragonadal androgen may contribute to the progression of castration-resistant prostate cancer. We evaluated whether abiraterone acetate, an inhibitor of androgen biosynthesis, prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received chemotherapy. METHODS: We randomly assigned, in a 2:1 ratio, 1195 patients who had previously received docetaxel to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). The primary end point was overall survival. The secondary end points included time to prostate-specific antigen (PSA) progression (elevation in the PSA level according to prespecified criteria), progression-free survival according to radiologic findings based on prespecified criteria, and the PSA response rate. RESULTS: After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate-prednisone group than in the placebo-prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001). Data were unblinded at the interim analysis, since these results exceeded the preplanned criteria for study termination. All secondary end points, including time to PSA progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months vs. 3.6 months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the treatment group. Mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, were more frequently reported in the abiraterone acetate-prednisone group than in the placebo-prednisone group. CONCLUSIONS: The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy. (Funded by Cougar Biotechnology; COU-AA-301 ClinicalTrials.gov number, NCT00638690.).

Prostate-cancer-specific survival and clinical progression-free survival in men with prostate cancer treated intermittently with testosterone-inactivating pharmaceuticals.

OBJECTIVES: More than 85% of men with prostate cancer die of other causes. An effective method is needed to distinguish fatal forms of prostate cancer from benign variants. METHODS: We performed a retrospective chart review from a medical oncology practice specializing in prostate cancer. All men with negative bone scans, prostate-specific antigen (PSA) level less than 100 ng/mL, adequate records for review, and who started taking testosterone inactivating pharmaceutical (TIP) agents before January 2000 were included in the study. Six factors were evaluated as potential predictors of prostate cancer-specific mortality: PSA nadir greater than 0.05 ng/mL while taking TIP, PSA doubling time of less than 12 months, Gleason score, stage, baseline PSA level greater than 20 ng/mL, and age. RESULTS: The study criteria were met by 160 men. The median follow-up was 10 years. The median age, PSA level, PSA nadir, and PSA doubling time was 65.6 years, 9.6 ng/mL, 0.03 ng/mL, and 10 months, respectively. Of the 160 men, 39 died of prostate cancer. Death from prostate cancer was far more common (78% versus 11%) and accelerated (median of 4 years versus 7 years) for men with a PSA nadir greater than 0.05 ng/mL than for those with a lower nadir. Multivariate Cox regression analysis indicated that the hazard ratio for prostate cancer-specific mortality in men with a PSA nadir greater than 0.05 ng/mL was 11.6 (P <0.0001). The hazard ratio for men with a PSA doubling time of less than 12 months was 2.9 (P = 0.04). Gleason score, stage, baseline PSA level greater than 20 ng/mL, and age were not statistically significant. CONCLUSIONS: Of the factors studied, the PSA nadir while taking a TIP was the best predictor of prostate cancer-specific mortality.