Niraparib plus abiraterone acetate with prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: second interim analysis of the randomized phase III MAGNITUDE trial.

BACKGROUND: Patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA alterations have poor outcomes. MAGNITUDE found patients with homologous recombination repair gene alterations (HRR+), particularly BRCA1/2, benefit from first-line therapy with niraparib plus abiraterone acetate and prednisone (AAP). Here we report longer follow-up from the second prespecified interim analysis (IA2). PATIENTS AND METHODS: Patients with mCRPC were prospectively identified as HRR+ with/without BRCA1/2 alterations and randomized 1 : 1 to niraparib (200 mg orally) plus AAP (1000 mg/10 mg orally) or placebo plus AAP. At IA2, secondary endpoints [time to symptomatic progression, time to initiation of cytotoxic chemotherapy, overall survival (OS)] were assessed. RESULTS: Overall, 212 HRR+ patients received niraparib plus AAP (BRCA1/2 subgroup, n = 113). At IA2 with 24.8 months of median follow-up in the BRCA1/2 subgroup, niraparib plus AAP significantly prolonged radiographic progression-free survival {rPFS; blinded independent central review; median rPFS 19.5 versus 10.9 months; hazard ratio (HR) = 0.55 [95% confidence interval (CI) 0.39-0.78]; nominal P = 0.0007} consistent with the first prespecified interim analysis. rPFS was also prolonged in the total HRR+ population [HR = 0.76 (95% CI 0.60-0.97); nominal P = 0.0280; median follow-up 26.8 months]. Improvements in time to symptomatic progression and time to initiation of cytotoxic chemotherapy were observed with niraparib plus AAP. In the BRCA1/2 subgroup, the analysis of OS with niraparib plus AAP demonstrated an HR of 0.88 (95% CI 0.58-1.34; nominal P = 0.5505); the prespecified inverse probability censoring weighting analysis of OS, accounting for imbalances in subsequent use of poly adenosine diphosphate-ribose polymerase inhibitors and other life-prolonging therapies, demonstrated an HR of 0.54 (95% CI 0.33-0.90; nominal P = 0.0181). No new safety signals were observed. CONCLUSIONS: MAGNITUDE, enrolling the largest BRCA1/2 cohort in first-line mCRPC to date, demonstrated improved rPFS and other clinically relevant outcomes with niraparib plus AAP in patients with BRCA1/2-altered mCRPC, emphasizing the importance of identifying this molecular subset of patients.

Clinical outcomes in men of diverse ethnic backgrounds with metastatic castration-resistant prostate cancer.

BACKGROUND: We have shown previously in multivariable analysis that black men had 19% lower risk of death than white men with metastatic castration-resistant prostate cancer (mCRPC) treated with a docetaxel and prednisone (DP)-based regimen. The primary goal of this analysis was to compare progression-free survival (PFS), biochemical PFS, ≥50% decline in prostate-specific antigen (PSA) from baseline and objective response rate (ORR) in white, black and Asian men with mCRPC treated with a DP-based regimen. PATIENTS AND METHODS: Individual patient data from 8820 mCRPC men randomized on nine phase III trials to a DP-containing regimen were combined. Race used in the analysis was based on self-report. End points were PFS, biochemical PSA, ≥50% decline in PSA from baseline and ORR. The proportional hazards and the logistic regression models were employed to assess the prognostic importance of race in predicting outcomes adjusting for established prognostic factors. RESULTS: Of 8820 patients, 7528 (85%) were white, 500 (6%) were black, 424 were Asian (5%) and 368 (4%) had race unspecified. Median PFS were 8.3 [95% confidence interval (CI) 8.2-8.5], 8.2 (95% CI 7.4-8.8) and 8.3 (95% CI 7.6-8.8) months in white, black and Asian men, respectively. Median PSA PFS were 9.9 (95% CI 9.7-10.4), 8.5 (95% CI 8.0-10.3) and 11.1 (95% CI 9.9-12.5) months in white, black and Asian men, respectively. CONCLUSIONS: We observed no differences in clinical outcomes by race and ethnic groups in men with mCRPC enrolled on these phase III clinical trials with DP.

Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer.

BACKGROUND: In the SPARTAN study, compared with placebo, apalutamide added to ongoing androgen deprivation therapy significantly prolonged metastasis-free survival (MFS) and time to symptomatic progression in patients with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC). Overall survival (OS) results at the first interim analysis (IA1) were immature, with 104 of 427 (24%) events required for planned final OS analysis. Here, we report the results of a second pre-specified interim analysis (IA2). METHODS: One thousand two hundred and seven patients with nmCRPC were randomized 2 : 1 to apalutamide (240 mg daily) or placebo. The primary end point of the study was MFS. Subsequent therapy for metastatic CRPC was permitted. When the primary end point was met, the study was unblinded. Patients receiving placebo who had not yet developed metastases were offered open-label apalutamide. At IA2, pre-specified analysis of OS was undertaken, using a group-sequential testing procedure with O'Brien-Fleming-type alpha spending function. Safety and second progression-free survival (PFS2) were assessed. RESULTS: Median follow-up was 41 months. With 285 (67% of required) OS events, apalutamide was associated with an improved OS compared with placebo (HR 0.75; 95% CI 0.59-0.96; P = 0.0197), although the P-value did not cross the pre-specified O'Brien-Fleming boundary of 0.0121. Apalutamide improved PFS2 (HR 0.55; 95% CI 0.45-0.68). At IA2, 69% of placebo-treated and 40% of apalutamide-treated patients had received subsequent life-prolonging therapy for metastatic CRPC. No new safety signals were observed. CONCLUSION: In patients with nmCRPC, apalutamide was associated with a 25% reduction in risk of death compared with placebo. This OS benefit was observed despite crossover of placebo-treated patients and higher rates of subsequent life-prolonging therapy for the placebo group.

Management of patients with advanced prostate cancer: recommendations of the St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) 2015.

The first St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) Expert Panel identified and reviewed the available evidence for the ten most important areas of controversy in advanced prostate cancer (APC) management. The successful registration of several drugs for castration-resistant prostate cancer and the recent studies of chemo-hormonal therapy in men with castration-naïve prostate cancer have led to considerable uncertainty as to the best treatment choices, sequence of treatment options and appropriate patient selection. Management recommendations based on expert opinion, and not based on a critical review of the available evidence, are presented. The various recommendations carried differing degrees of support, as reflected in the wording of the article text and in the detailed voting results recorded in supplementary Material, available at Annals of Oncology online. Detailed decisions on treatment as always will involve consideration of disease extent and location, prior treatments, host factors, patient preferences as well as logistical and economic constraints. Inclusion of men with APC in clinical trials should be encouraged.

Inhibition of the androgen receptor by mineralocorticoids at levels physiologically achieved in serum in patients treated with abiraterone acetate.

BACKGROUND: Abiraterone acetate (AA), a highly potent CYP17A1 inhibitor, has demonstrated marked clinical benefit in patients with metastatic castration-resistant prostate cancer (CRPC). Phase I trials of AA without prednisone showed significant elevation of serum mineralocorticoid concentrations. The aim of this study was to elucidate the biological significance of elevated mineralocorticoid levels on androgen receptor (AR) activity in prostate cancer (PC) cells. METHODS: Fluorescence resonance energy transfer (FRET) assay was used to assess the effect of mineralocorticoids on androgen-induced conformational change of the AR. LAPC4, LNCaP and LN-AR cells that were cultured and treated with androgens were exposed to mineralocorticoids at varying concentrations, including levels measured in the serum of AA-treated patients in a phase I trial. AR-dependent transcriptional activity and cell growth were measured in these cell lines to determine the biological impact of mineralocorticoids on PC cells. RESULTS: Corticosterone (CS) and deoxycorticosterone (DOC) inhibited androgen-induced conformational change of the AR in the FRET assay. CS inhibited AR-dependent transcriptional activity and cell growth at concentrations comparable to those measured in the serum of AA-treated patients. DOC inhibited AR transcriptional activity and cell growth at 10-fold greater concentrations than measured in the serum of AA-treated patients. CONCLUSIONS: Mineralocorticoids directly inhibit androgen-induced conformational change of the AR. CS inhibits AR transcriptional activity and PC cell growth at concentrations found in the serum of patients treated with AA. Further investigation of the potential therapeutic implications of mineralocorticoids in AA-treated CRPC patients is warranted.

Time to disease-related pain and first opioid use in patients with metastatic castration-resistant prostate cancer treated with sipuleucel-T.

BACKGROUND: Sipuleucel-T has demonstrated improved overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC). This analysis examined the effect of sipuleucel-T on time to disease-related pain (TDRP) and time to first use of opioid analgesics (TFOA) in mCRPC using data pooled from three randomized phase III studies in men with asymptomatic or minimally symptomatic mCRPC (D9901 (NCT00005947), D9902A (NCT01133704), D9902B (IMPACT; NCT00065442)). METHODS: Four-hundred and twenty-eight asymptomatic patients were analyzed for TDRP; 737 patients were analyzed for TFOA. Pain status was collected using logs adjudicated by blinded, independent reviewers. Opioid use for cancer-related pain was identified from medically reviewed reports of concomitant medication. Disease-related pain was defined as pain post enrollment. TDRP and TFOA were analyzed using the Kaplan-Meier method and Cox regression. RESULTS: Treatment with sipuleucel-T was not associated with a significant difference in TDRP (hazard ratio (HR)=0.819; 95% confidence interval (CI): 0.616-1.089; P=0.170; median TDRP 5.6 months for sipuleucel-T and 5.3 months for control, respectively), although 39.3% of sipuleucel-T-treated patients and 18.9% of control patients were pain-free at 12 months. However, there was a significant delay in TFOA with sipuleucel-T (HR=0.755; 95% CI: 0.579-0.985; P=0.038). Median TFOA for sipuleucel-T was 12.6, and 9.7 months for control, with 50.6% and 43.1% opioid-free at 12 months, respectively. Kaplan-Meier curves for both end points began to diverge at 6 months. CONCLUSIONS: Sipuleucel-T was associated with longer TFOA but not significantly longer TDRP. Both end points demonstrated evidence of a delayed treatment effect, consistent with an active immunotherapy.

A phase II trial of cisplatin (C), gemcitabine (G) and gefitinib for advanced urothelial tract carcinoma: results of Cancer and Leukemia Group B (CALGB) 90102.

BACKGROUND: This phase II trial (Cancer and Leukemia Group B 90102) sought to determine the efficacy of cisplatin, standard infusion of gemcitabine and gefitinib in patients with advanced urothelial carcinoma. PATIENTS AND METHODS: Eligible patients had previously untreated measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status of zero to two and creatinine clearance >50 ml/min. Treatment consisted of cisplatin 70 mg/m(2) day 1 and gemcitabine 1000 mg/m(2) on days 1 and 8 given every 3 weeks concurrent with gefitinib 500 mg/day orally for six cycles. Maintenance gefitinib 500 mg/day was continued for responding or stable disease. RESULTS: Fifty-four of 58 patients were assessable. Twelve patients (22%) had node-only disease, and 25 (46%) had an ECOG performance status of zero. There were 23 objective responses for an overall response rate of 42.6% [95% confidence interval (CI) 29.2% to 56.8%]. The median survival time was 15.1 months (95% CI 11.1-21.7 months) and the median time to progression was 7.4 months (95% CI 5.6-9.2 months). CONCLUSIONS: The combination of cisplatin, gemcitabine and gefitinib is well tolerated and active in advanced transitional cell carcinoma. The addition of gefitinib does not appear to improve response rate or survival in comparison to historical controls of cisplatin and gemcitabine alone.

Phase II study of bortezomib in patients with previously treated advanced urothelial tract transitional cell carcinoma: CALGB 90207.

BACKGROUND: There is no standard second-line treatment for advanced urothelial carcinoma (UC). Response rates to second-line chemotherapy for advanced UC are low and response duration is short. Bortezomib is a proteasome inhibitor with preclinical activity against UC. PATIENTS AND METHODS: Treatment consisted of bortezomib 1.3 mg/m(2) i.v. twice weekly for two consecutive weeks, followed by a 1-week break. The primary end point was objective response rate (complete response + partial response) by Response Evaluation Criteria in Solid Tumors criteria. Secondary end points included safety, toxicity, and progression-free and overall survival. RESULTS: In all, 25 patients with advanced UC previously treated with combination chemotherapy were enrolled in a multi-institutional single-arm trial from December 2003 through April 2005. Only 29% of patients had node-only metastases. Grade 3/4 drug-related toxic effects included thrombocytopenia (4%), anemia (8%), lymphopenia (8%), sensory neuropathy (6%), hyperglycemia (4%), hypernatremia (4%), fatigue (4%), neuropathic pain (6%), dehydration (4%), and vomiting (4%). No objective responses were observed [95% confidence interval (CI) = 0-12]. The median time to progression was 1.4 months (95% CI = 1.1-2.0 months), and the median survival time was 5.7 months (95% CI = 3.6-8.4 months). There were no treatment-related deaths. CONCLUSION: Although bortezomib is well tolerated, it does not have antitumor activity as second-line therapy in UC.

Androgen deprivation therapy in locally advanced and metastatic prostate cancer.

Numerous studies have been performed testing the efficacy of early androgen deprivation (AD) in patients with localized and locally advanced prostate cancer. A systematic review of recent publications that report on the use of AD in non-metastatic prostate cancer patients was performed. Recently published mature randomized trials of AD plus local therapy were evaluated plus 2 large datasets on the use of AD for patients with serologic relapse after local therapy. Four mature randomized studies demonstrate an overall survival benefit to the use of AD in conjunction with definitive local therapy (3 with radiation and 1 with surgery). One retrospective analysis suggests that AD administered at early after serologic progression improves overall survival, and one retrospective analysis shows a reduction in metastasis-free survival but has not yet shown an overall survival benefit. In virtually all analyses, patients with high-risk features benefited from early AD when compared to deferred therapy. Consideration of AD is therefore warranted early in the clinical course of high-risk patients.

The evolving role of androgen deprivation therapy in the management of prostate cancer.

Androgen deprivation therapy (ADT) plays a central role in the management of prostate cancer. ADT is the mainstay of treatment for metastatic disease; the most common method is gonadal suppression via luteinizing hormone release hormone (LH) agonists, with or without antiandrogens. Antiandrogen monotherapy remains investigational, as is the appropriate role of 5alphareductase inhibition for prostate cancer. Intermittent ADT offers the promise of improved quality of life and reduced cost without a decrease found to date in oncologic efficacy. A growing menu of options exists for secondary androgen deprivation after disease progression on primary therapy: these include high-dose antiandrogens, estrogens, and adrenal androgen suppressants. ADT is being used with increasing frequency as primary monotherapy in patients with localized disease, but only small, nonrandomized studies of highly selected patients have been reported to date. Neoadjuvant ADT (NADT) has been demonstrated in prospective, multi-institutional trials to improve outcomes for patients with high-risk or locally advanced disease undergoing external-beam radiotherapy. Trials for patients with lower-risk, localized disease are still ongoing. Neoadjuvant therapy does not improve outcomes for patients with localized disease opting for radical prostatectomy (RP) and has not been well studied in association with brachytherapy. The side effects of ADT can be managed increasingly successfully; in particular, the introduction of zoledronate may reduce the impact of ADT-associated osteoporosis. Finally, contemporary practice pattern data suggest that use of ADT is increasing across patient risk groups, both in contexts where such therapy is well supported by current evidence and in others where it is not.

Docetaxel, estramustine, plus trastuzumab in patients with metastatic androgen-independent prostate cancer.

The incidence of human epidermal growth factor receptor 2 (HER2) protein overexpression and its prognostic value are not well characterized in patients with prostate cancer. A phase I study was designed to evaluate docetaxel/estramustine plus trastuzumab, a humanized monoclonal antibody that binds to the HER2 receptor, in patients with metastatic androgen-independent prostate cancer (AIPC). HER2 positivity was not required because safety was the primary endpoint. Patients received oral estramustine 280 mg three times daily (days 1 to 5); docetaxel, 70 mg/m(2) intravenously (day 2); and trastuzumab, 2 mg/kg intravenously (days 2, 9, and 19), every 21 days until the disease progressed or toxicity became unacceptable. This regimen was well tolerated among the first 13 treated patients. Grade 4 neutropenia was seen in 10% of administered cycles. There were two episodes of febrile neutropenia and two thrombembolic events. Of the 13 patients evaluable for prostate-specific antigen (PSA) response, nine (69%) experienced a decrease in PSA level of >50%. Two (33%) of six patients with measurable disease had objective responses, and one complete response was seen on bone scan. Docetaxel/estramustine/trastuzumab appears to be a safe combination when used in the treatment of metastatic AIPC. The response data are too preliminary for speculation about the relative benefits of this 3-drug regimen compared with the combination of only docetaxel and estramustine in this clinical setting.

HER2 protein expression and gene amplification in androgen-independent prostate cancer.

The role of the HER2 receptor remains uncertain in the pathogenesis and progression of human prostate cancer. Previous studies have reported widely divergent rates for HER2 expression in primary prostate tumors, probably owing to significant methodologic differences in the studies. Few data exist about the frequency of HER2 protein overexpression and gene amplification in androgen-independent prostate cancer (AIPC), although recent xenograft models suggest HER2 expression may be up-regulated in the transition from androgen-dependent to androgen-independent disease. We studied the role of HER2 protein in AIPC by immunohistochemical and fluorescence in situ hybridization (FISH) analyses on AIPC specimens using well-characterized and validated reagents. Fourteen (36%) of 39 specimens expressed HER2; however, only 2 (5%) had moderate (2+) expression, and 2 (5%) had high-level (3+) expression. Two (6%) of 36 specimens had gene amplification by FISH. These data suggest that HER2 protein overexpression and gene amplification are relatively uncommon in AIPC.

Immunotherapy for prostate cancer.

The components of an effective immune response have been elucidated in recent years. An understanding of the dysfunction of the immune response in cancer in one or more of these components has led to a variety of immunotherapeutic approaches. These therapeutic strategies are designed to stimulate dendritic cell proliferation, promote antigen uptake and processing, stimulate an effector cell response via direct antigen presentation, or target tumor cells via antibody therapy. Many approaches in prostate cancer have demonstrated successful induction of the desired immune response. Limited clinical success has also been seen.

Androgen deprivation therapy for patients with clinically localized (stages T1 to T3) prostate cancer and for patients with biochemical recurrence after radical prostatectomy.

Recently published studies suggest a benefit for androgen deprivation therapy (ADT) delivered early in the course of prostate cancer. However, the use of ADT specifically in patients with clinically localized disease or biochemical-disease recurrence after local therapy is not well defined. Potential candidates for primary ADT include patients who are poor candidates for definitive local therapy because of advanced age or comorbid conditions, as well as patients with significant local disease who refuse standard therapy. Treatment strategies designed to minimize the side effects of prolonged therapy, such as intermittent ADT or antiandrogen monotherapy, show promise as alternatives to continuous ADT in some patients. The role of ADT in patients with clinically localized and recurrent prostate cancer, whether it is delivered in a continuous or intermittent fashion, must be determined in randomized, prospective trials.

Intermittent androgen deprivation: update of cycling characteristics in patients without clinically apparent metastatic prostate cancer.

OBJECTIVES: To update the cycling characteristics and patterns of treatment in patients receiving intermittent androgen deprivation (IAD) for clinically localized and recurrent prostate cancer. METHODS: We report our experience with 61 patients treated with IAD. Thirty-four patients had received no prior treatment, and 27 had developed recurrent disease after previous local therapy. No patient had clinically apparent metastatic disease before the initiation of therapy. The mean and median serum prostate-specific antigen (PSA) level before treatment was 25.3 ng/mL and 16.0 ng/mL, respectively (range 0.5 to 190 ng/mL). For each cycle, androgen deprivation was continued until PSA became undetectable or a nadir level was reached. Patients were then observed without treatment, and therapy was reinstituted after the serum PSA value reached a predetermined level. Patients were no longer eligible to cycle off treatment when their serum PSA increased despite ongoing androgen deprivation or if any objective evidence of disease progression was present on imaging studies. RESULTS: Follow-up ranged from 7 to 60 months (mean 30) from the start of treatment. Patients received from one to five treatment cycles (median two), with a median cycle length of 14 months. The median nadir serum PSA level during androgen deprivation was 0.01 ng/mL and was reached within an average of 6 months (range 4 to 9) after beginning treatment. Patients spent an average of 45% of the time not receiving therapy, but the time off therapy decreased as the number of treatment cycles increased. Five patients (8.1%) demonstrated progressive disease, with a median time to progression of 48 months. When examining the cycling characteristics of these patients, no consistent pattern of failure emerged. CONCLUSIONS: IAD appears to be a viable treatment option in select patients with localized prostate cancer. With each consecutive cycle, the amount of time the patient was not receiving therapy decreased, despite achieving a low nadir PSA. Longer follow-up with more patients failing IAD will be required before clear patterns of failure emerge in these patients.

Prognostic significance of plasma vascular endothelial growth factor levels in patients with hormone-refractory prostate cancer treated on Cancer and Leukemia Group B 9480.

PURPOSE: Plasma vascular endothelial growth factor (VEGF) levels are significantly elevated in patients with hormone-refractory prostate cancer (HRPC) compared with patients with localized disease and have been associated with disease progression in other cancer patient populations. Therefore, we measured VEGF levels in plasma prospectively collected from patients enrolled in Cancer and Leukemia Group B 9480, an intergroup study of suramin in patients with HRPC, to determine whether these levels had prognostic significance. EXPERIMENTAL DESIGN: Pretreatment plasma was collected from patients with HRPC enrolled in Cancer and Leukemia Group B 9480. In a subset of samples representative of the entire cohort, plasma VEGF levels were determined in duplicate using a Quantiglo chemiluminescent ELISA kit (R&D Systems, Minneapolis, MN). Statistical analyses were performed to determine the correlation between pretreatment plasma VEGF levels and time of overall survival. The proportional hazards model was used to assess the prognostic significance of various cut points in multivariate models. RESULTS: Plasma VEGF levels in this population ranged from 4-885 pg/ml, with a median level of 83 pg/ml. As a continuous variable, plasma VEGF levels inversely correlated with survival time (P = 0.002). Using various exploratory cut points, plasma VEGF levels appeared to correlate with survival. In multivariate models in which other prognostic factors (serum prostate-specific antigen, alkaline phosphatase, evidence of measurable disease, and hemoglobin) were included, plasma VEGF levels were significant at various cut points tested. CONCLUSION: Although these data are exploratory and need to be confirmed in an independent data set, they suggest that VEGF may have clinical significance in patients with HRPC.

Prognostic significance of reverse transcriptase polymerase chain reaction for prostate-specific antigen in men with hormone-refractory prostate cancer.

PURPOSE: To evaluate the prognostic significance of reverse transcriptase polymerase chain reaction (RT-PCR) detection of prostate-specific antigen (PSA) mRNA in the blood of men with hormone-refractory prostate cancer (HRPC). PATIENTS AND METHODS: Peripheral blood was obtained from 193 men enrolled on Cancer and Leukemia Group B Study 9480, a prospective randomized comparison of three doses of suramin. RNA was isolated from the samples and assayed for the presence of PSA transcripts by RT-PCR. RESULTS: RNA could be isolated in 156 (83%) of samples. PSA transcripts as measured by RT-PCR were detectable in 75 (48%) of the 156 patients. The median survival for those patients in whom no transcripts were detectable was 18 months (95% confidence interval [CI], 14 to 22 months) compared with 13 months (95% CI, 11 to 15 months) (P =.004) for those in whom transcripts were detectable. In a multivariate analysis in which other factors predictive of survival were used, RT-PCR for PSA provided independent prognostic information. CONCLUSION: RT-PCR for PSA predicts survival duration in a population of men with HRPC.