Metastatic Castration-refractory Prostate Cancer Research Articles

The impact of progression-directed therapy on survival in metastatic castration-refractory prostate cancer: MEDCARE phase 3 trial.

Metastatic castration-refractory prostate cancer (mCRPC) presents a therapeutic challenge despite advancements in treatment. Once mCRPC is attained, patients face limited survival prospects. Next-line systemic treatment (NEST) is the standard of care for progressive mCRPC, encompassing various therapeutic options with associated toxicity and costs. In patients with oligoprogressive mCRPC, data suggest that progression-directed therapy (PDT), such as metastasectomy or stereotactic body radiotherapy, delays the initiation of NEST. The MEDCARE phase III trial aims to assess the impact of PDT on overall survival (OS) in oligoprogressive mCRPC. In this multicentric, randomised, prospective trial, we aim to randomise 246 patients in 1:1 allocation ratio between the standard-of-care therapy (surveillance or NEST) or PDT while continuing the current systemic treatment. Patients will be stratified based on number of progressive lesions (one vs ≥one), location of progressive lesions (local recurrence, N or M1a vs M1b or M1c) and previous systemic therapy (palliative androgen-deprivation therapy [pADT] vs pADT + androgen receptor-targeted agent or patients who received docetaxel in the past). The primary endpoint is OS, and the secondary endpoints include quality of life, radiographic progression-free survival (PFS), modified PFS, prostate cancer-specific survival and PDT-induced toxicity. This is the first randomised phase 3 trial in the setting of PDT in patients with oligoprogressive mCRPC with OS as the primary endpoint.

When repeated biopsy dramatically changes treatment tactics in metastatic castration-refractory prostate cancer with neuroendocrine transformation: clinical case and literature review

When repeated biopsy dramatically changes treatment tactics in metastatic castration-refractory prostate cancer with neuroendocrine transformation: clinical case and literature review

Progression-Directed Therapy in Oligoprogressive Castration-Refractory Prostate Cancer: Results of the Prospective Single-Arm Phase II MEDCARE Trial

Next-line systemic treatment (NEST) for progressive metastatic castration-refractory prostate cancer (mCRPC) is associated with significant costs and non-negligible toxicity. For oligoprogressive (OP) disease, defined as the appearance of up to 3 progressive and/or new lesions and/or local recurrence on conventional imaging, progression-directed therapy (PDT) may prolong the efficacy of ongoing systemic therapy and delay initiation of NEST. To investigate whether PDT could postpone NEST in patients with OP mCRPC in the prospective, single-arm, monocentric MEDCARE trial. We enrolled patients with OP mCRPC while on ongoing treatment with androgen deprivation therapy (ADT), with or without an androgen receptor-targeted agent (ARTA). Progression was detected with conventional imaging (bone scan and CT of MRI). A history of docetaxel treatment was allowed. All progressive lesions had to be treatable with PDT, either (stereotactic body) radiation therapy ((SB)RT) or metastasectomy. Repeated PDT was allowed at the time of further oligoprogression. The primary endpoint was NEST-free survival. Secondary outcomes of the trial included clinical progression-free survival (cPFS), prostate cancer specific survival (PCSS), overall survival (OS) as well as acute and late toxicity. Between January 2020 and January 2021, 20 patients were included. Median age was 74 years. Median PSA level and PSA doubling at the time of inclusion were 4 ng/ml (IQR 2-11) and 4 months (IQR 3-5), respectively. Median follow-up was 28 months (IQR 5-33). A total of 31 lesions were treated with SBRT to 22.5-30 Gy in 3-5 fractions of 7.5-10 Gy. 11, 7 and 2 patients had one, two and three concurrent lesions respectively. At the time of inclusion, sixteen patients had bone metastases, two patients had only lymph node metastases, one patient a liver metastasis and one patient had local recurrence. If the primary tumor had not yet been treated, local radiotherapy to the prostate was given (n = 5). Five patients received repeated PDT for oligoprogression. Ongoing therapy at time of inclusion was ADT (n = 8) alone or ADT + ARTA (n = 12). The number of different systemic treatment lines received before inclusion was one, two and three for 5, 13 and 2 patients respectively. The median NEST-free survival was 17 months (95% CI: 9-25). The median cPFS was 6 months (95% CI: 5-7). The median PCSS was not reached while the median OS was 29 months (95% CI, 28-30). At last follow-up, 9 patients had died, of whom 6 due to progressive prostate cancer and 3 due to rapid progression of a second primary tumor (small cell lung cancer, leiomyosarcoma and acute myeloid leukemia). PDT was well tolerated with no acute nor late grade ≥3 toxicity. In OP mCRPC patients, PDT postpones the need for NEST for almost 1.5 years without inducing severe toxicity.

Novel hormone treatment for advanced prostate cancer

The systemic treatment of advanced prostate cancer (PCa) has undergone an absolute revolution in the past decade. Numerous new substances have been approved for all stages of advanced disease and treatment has been increasingly intensified. The focus continues to be on substances with an effect on the androgen receptor axis. In this review, approved treatment options for metastatic hormone-sensitive PCa (mHSPC), non-metastatic castration-refractory PCa (nmCRPC) and metastatic castration-refractory PCa (mCRPC) are summarized. A special focus is on novel hormone therapeutic agents. Based on recent trial data, potential triple combinations for mHSPC as well as treatment sequence options and novel targeted agents for mCRPC are also highlighted.

Systemic inflammatory biomarkers as predictive and prognostic factors in men with metastatic castration-refractory prostate cancer treated with docetaxel therapy: a comprehensive analysis in a German real-world cohort

PurposeAdvances in therapy of metastatic castration-refractory prostate cancer (mCRPC) resulted in more therapeutic options and led to a higher need of predictive/prognostic biomarkers. Systemic inflammatory biomarkers could provide the basis for personalized treatment selection. This study aimed to assess the modified Glasgow Prognostic Score (mGPS), the neutrophile-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR) and the systemic immune-inflammation index (SII) in men with mCRPC under docetaxel.MethodsPatients with mCRPC and taxane chemotherapy at a tertiary care centre between 2010 and 2019 were screened retrospectively. The biomarkers mGPS, NLR, PLR and SII were assessed and analyzed for biochemical/radiologic response and survival.ResultsWe included 118 patients. Of these, 73 (61.9%) had received docetaxel as first-line, 31 (26.2%) as second-line and 14 (11.9%) as third-line treatment. For biochemical response, mGPS (odds ratio (OR) 0.54, p = 0.04) and PLR (OR 0.63, p = 0.04) were independent predictors in multivariable analysis. SII was significant in first-line cohort only (OR 0.29, p = 0.02). No inflammatory marker was predictive for radiologic response. In multivariable analysis, mGPS and NLR (hazard ratio (HR) 1.71 and 1.12, both p < 0.01) showed significant association with OS in total cohort and mGPS in the first-line cohort (HR 2.23, p < 0.01). Haemoglobin (Hb) and alkaline phosphatase (AP) showed several significant associations regarding 1 year, 3 year, OS and biochemical/radiologic response.ConclusionsPre-treatment mGPS seems a promising prognostic biomarker. A combination of mGPS, NLR and further routine markers (e.g., Hb and AP) could yield optimized stratification for treatment selection. Further prospective and multicentric assessment is needed.

Cabazitaxel versus docetaxel for treatment of metastatic castrate refractory prostate cancer.

ObjectivesTo assess cabazitaxel versus docetaxel re‐challenge for the treatment of metastatic castrate refractory prostate cancer (CRPC) patients previously treated with docetaxel at inception of primary hormone therapy.Patients and MethodsThe CANTATA trial was a prospective, two‐arm, open‐label, phase II study conducted in eight UK centres. Patients over the age of 18, with histologically proven, metastatic prostate cancer who had been previously treated with up to 6 cycles of docetaxel as part of the STAMPEDE trial (or treated with the same drug outside of the trial at primary diagnosis) and had a performance status (PS) of 0–2, were eligible. Patients who progressed during primary treatment with docetaxel or had received prior systemic chemotherapy were excluded. Cabazitaxel (25 mg/m2) or docetaxel (75 mg/m2) was administered via intravenous infusion every 3 weeks with oral prednisolone (10 mg) for up to 10 cycles, until disease progression, death or unacceptable toxicity. The primary outcome was clinical progression‐free survival (PFS) as defined by either date of pain progression, date of a cancer‐related skeletal‐related event, or date of death from any cause. Analyses were by intention to treat. EudraCT number: 2012‐003835‐40ResultsBetween 7 March 2013 and 4 January 2016, 15 patients with a median age of 70 years (range 54–76) were recruited; seven received cabazitaxel, eight docetaxel. The study was halted due to slow accrual. The median clinical PFS time in the cabazitaxel group was 6.2 months compared with 8.4 for the docetaxel group (95% confidence intervals were not reached due to the small number of patients). A total of 13 serious adverse events were reported.ConclusionDue to the low number of patients recruited, meaningful comparisons could not be made. However, toxicity was in line with known outcomes for these agents, demonstrating it is feasible and safe to deliver chemotherapy to men relapsing with CRPC after upfront chemotherapy.

Estimation of Utility Weights for Prostate-related Health States in Korea.

ObjectivesVery limited previous research has investigated the utility weights of prostate-related diseases in the general population in Korea. The purpose of this study was to calculate the utility of prostate-related health states in the Korean general public using the standard gamble (SG) method.MethodsSeven health states for hypothetical prostate cancers, 1 for benign prostate hyperplasia, and 1 for erectile dysfunction were developed based on patient education material and previous publications. In total, 460 responses from the Korean general population were used to analyze the utility of prostate-related health states. Computer-assisted personal interviews were conducted, and utility values were measured using a visual analogue scale (VAS) and SG. Mean utility values were calculated for each prostate-related health state.ResultsThe mean utility values of prostate cancer derived from SG ranged from 0.281 (metastatic castration-refractory prostate cancer) to 0.779 (localized prostate cancer requiring prostatectomy). The utility value of benign prostate hyperplasia was 0.871, and that of erectile dysfunction was 0.812. The utility values obtained using the SG method in all conditions were higher than the values obtained by VAS. There were no significant demographic variables affecting utility values in multivariate analysis.ConclusionsOur findings might be useful for economic evaluation and utility calculation of screening and interventions for prostate-related conditions in the general population.

Metastasis-Directed Therapy for Oligoprogressive Castration-Resistant Prostate Cancer ― Preliminary Results of the Prospective, Single-Arm MEDCARE Trial

In metastatic castration-refractory prostate cancer (mCRPC), clinical progression usually implies the start of a new systemic treatment-line. When clinical progression is limited to a few new and/or progressive lesions, while all other lesions are still responsive to ongoing treatment, the term 'oligoprogression' is used. Retrospective data demonstrated that metastasis-directed therapy (MDT) to the oligoprogressive lesions substantially postponed the start of next-line systemic treatment (NEST). Based on these results, the prospective, single-arm MEDCARE trial was initiated.MEDCARE is a prospective, single-arm, monocentric pilot-study, investigating the use of MDT in oligoprogressive mCRPC. Oligoprogression was defined as ≤3 new and/or progressive metastatic lesions or local progression (counting as 1 new lesion) diagnosed on CT or bone scan. Additional MRI was allowed for confirmation. All patients also underwent an 18F PSMA PET-CT as investigational imaging, to assess its predictive value and impact on treatment policy. Ongoing systemic treatment at the time of oligoprogression was continued. MDT consisted of stereotactic body radiation therapy (SBRT) or metastasectomy. The primary endpoint of the trial was NEST-free survival, calculated from the last day of MDT until the start of NEST. Clinical progression-free survival (cPFS) and toxicity scoring with CTCAE v4 scoring were secondary endpoints.Between January 2020 and January 2021, 20 patients were included in the trial. Median age at time of inclusion was 74 years (IQR 67-78). Median PSA and PSA doubling time were 4 ng/ml (IQR 2-11) and 4 months (IQR 3-5), respectively. Eleven patients had 1 progressive lesion on conventional imaging, 7 patients had 2 progressive lesions and 2 patients had 3 progressive lesions. The most frequent location of progressive lesions was the bone (16/20). One patient was treated for a progressive liver metastasis, and one patient presented with progression in the prostatic fossa. Two more patients had a combination of progression in pelvic and retroperitoneal lymph nodes (N1/M1a disease). All patients with progressive metastatic lesions were treated with SBRT (30 Gy in 3 fractions (BED 130 Gy for a/b = 3). The patient with local progression was treated with conventional radiotherapy (77 Gy in 35 fractions (BED 133 Gy for a/b = 3)). At a median follow-up of 6 months (IQR 2-9), 8 patients experienced clinical progression, and five patients were started on NEST. Median NEST-FS was 12 months. Three patients died, 2 deaths were prostate cancer related and 1 patient died of small cell lung cancer. MDT was well tolerated, with 3 patients experiencing grade 1 toxicity, and two patients grade 2 toxicity (acute GU toxicity). There were no patients with grade 3 or higher toxicity.The first results of the MEDCARE trial (NCT04222634) investigating MDT in oligoprogressive CRPC are promising, with negligible toxicity.

LBA02-11 MASITINIB PLUS DOCETAXEL AS FIRST-LINE TREATMENT OF METASTATIC CASTRATE REFRACTORY PROSTATE CANCER: RESULTS FROM STUDY AB12003

You have accessJournal of UrologyLate-breaking Abstract II - Malignant1 Sep 2021LBA02-11 MASITINIB PLUS DOCETAXEL AS FIRST-LINE TREATMENT OF METASTATIC CASTRATE REFRACTORY PROSTATE CANCER: RESULTS FROM STUDY AB12003 Michel Pavic, Olivier Hermine, and Dominique Spaeth Michel PavicMichel Pavic More articles by this author , Olivier HermineOlivier Hermine More articles by this author , and Dominique SpaethDominique Spaeth More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002149.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Masitinib (MAS) is an oral, small molecule drug that targets mast cell and macrophage activity. These innate immune cells are critical components of the tumor microenvironment and are associated with prostate cancer progression. METHODS: AB12003 was a prospective, placebo (PBO) controlled, double blind, randomized, phase 3 trial, evaluating MAS (6.0 mg/kg/d) in combination with docetaxel (DTX) (IV 75 mg/m2 plus prednisone for up to 10 cycles) as a first-line treatment of metastatic castrate resistant prostate cancer (mCRPC). Eligible patients (pts) were chemo-naïve with confirmed mCRPC, who had progressed on previous abiraterone treatment or were indicated for DTX treatment, and had a ECOG ≤1. Primary analysis was performed on a pre-specified targeted subgroup, defined as pts with baseline alkaline phosphatase levels (ALP) ≤250 IU/ml, and on the overall population. Primary endpoint was progression free survival (PFS) (PCWG2 definition). The study was successful if improvement in median PFS relative to control reached a 3.9% level of significance for the target subgroup (alpha split with fallback procedure to conserve overall type-I error at 5% for the overall study cohort). RESULTS: A total of 714 pts were enrolled (safety population n=712). In the targeted (ALP ≤250) subgroup, MAS-DTX (n=225) showed significant benefit over PBO-DTX (n=225) with median PFS of 6.3 months (96.1% CI [5.6;7.6]) vs 5.4[4.6;6.0] months; p=0.0272. The hazard ratio (HR) was 0.79 [0.64;0.97], p=0.0087), a significant 21% reduction in risk of progression for MAS-DTX pts relative to control. Assessment of PFS rates was convergent with this primary outcome; 12, 18, and 24-month PFS rates showed significant 1.6-fold (p=0.0035), 1.9-fold (p=0.0001) and 1.9-fold (p=0.0028) improvement, respectively, in favor of MAS-DTX (ie, 32.0%, 27.6% and 23.1% for MAS-DTX vs 19.6%, 14.6% and 12.0% for PBO-DTX). There was no benefit on overall survival (OS) in the targeted subgroup. Regarding the overall population (ie, irrespective of ALP), no PFS or OS benefit was observed; median PFS for MAS-DTX (n=355) was 5.7 months (95% CI [4.9;6.3]) vs 5.4[4.6;5.9] months for PBO-DTX (n=357), p=0.2977. The proportion of pts presenting at least one adverse event (AE), severe AE or serious AE was respectively, 96.6%, 79.2% and 27.6% for MAS-DTX (n=355) vs 96.4%, 73.1% and 18.8% for PBO-DTX (n=357). CONCLUSIONS: The combination MAS (6.0 mg/kg/d) plus DTX may provide a new first-line treatment option for mCRPC pts with ALP ≤250 IU/ml. Source of Funding: AB Science, France © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e1179-e1179 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Michel Pavic More articles by this author Olivier Hermine More articles by this author Dominique Spaeth More articles by this author Expand All Advertisement Loading ...

Announcing the Lancet Commission on Prostate Cancer

Prostate cancer is the second most frequent cancer in men, and there were about 1·4 million new cases around the world in 2020. 1 Sung H Ferlay J Siegel RL et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021; (published online Feb 4.)https://doi.org/10.3322/caac.21660 Crossref PubMed Scopus (2010) Google Scholar , 2 Ferlay J Ervik M Lam F et al. Global Cancer Observatory: cancer today. https://gco.iarc.fr/todayDate: 2020 Date accessed: April 16, 2021 Google Scholar Prostate cancer accounts for an estimated 15% of all cancer cases in men worldwide and is the most common form of cancer in men in in 112 countries (figure). Globally, there are many hundreds of thousands of premature deaths from prostate cancer annually, 3 Bray F Ferlay J Soerjomataram I Siegel RL Torre LA Jemal A Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68: 394-424 Crossref PubMed Scopus (33702) Google Scholar and a huge toll in morbidity, particularly bone metastases leading to pain, fracture, and disability. 4 James N Pirrie S Pope A et al. TRAPEZE: a randomised controlled trial of the clinical effectiveness and cost-effectiveness of chemotherapy with zoledronic acid, strontium-89, or both, in men with bony metastatic castration-refractory prostate cancer. Health Technol Assess. 2016; 20: 1-288 Crossref PubMed Scopus (19) Google Scholar Curative treatment itself can also cause adverse effects on urinary and sexual function. 5 Hamdy FC Donovan JL Lane JA et al. 10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. N Engl J Med. 2016; 375: 1415-1424 Crossref PubMed Scopus (1360) Google Scholar There is a growing tension between the need to diagnose advanced disease early while not overdiagnosing lower risk disease that probably does not need treatment.

Randomized phase II trial of radium-223 (RA) plus enzalutamide (EZ) versus EZ alone in metastatic castration-refractory prostate cancer (mCRPC): Final efficacy and safety results.

135 Background: We previously reported that treatment with EZ+RA was associated with a decline in serum bone metabolism markers (BMM), which correlated with improved outcomes compared to EZ alone (Agarwal N et al, Clinical Cancer Research, 2020, PMID 31937614). Here we report the final efficacy and safety results for this trial. Methods: In this phase 2 trial (NCT02199197), patients (pts) with progressive mCRPC were treated with EZ (160 mg daily) ±RA (standard dose of 55 kBq/kg IV Q4 weeks x 6), until disease progression or unacceptable toxicities. Primary objectives of change in bone markers and safety have been reported previously. Secondary objectives included comparison of PSA progression free survival (PFS), overall survival (OS), and long term safety in all pts receiving RA+EZ vs EZ alone. Post hoc analysis included comparison of PSA-PFS2 (defined as time from start of protocol therapy to PSA progression on subsequent therapy or death whichever occurred earlier), time to subsequent/next therapy (TTNT), and long term safety. Survival analysis and log-rank tests was performed using the R statistical package v.4.0.2 ( https://www.r-project.org ). Statistical significance was defined as P&lt;0.05. Results: Between 08/2014 and 11/2017, 47 pts were eligible and enrolled. Median follow up was 22 months (range 3.2-71.5). Thirty-five pts received RA+EZ and 12 pts received EZ alone. Receipt of prior abiraterone was allowed and was balanced between two groups: 60% in RA+EZ vs. 64% in EZ pts. Final efficacy results: TTNT, PSA-PFS2 were significantly improved in the RA+EZ pts over EZ alone pts, and all other efficacy parameters were numerically improved in RA+EZ pts (Table). Final safety results: none of the 12 EZ alone pts had any fracture; two of 35 RA+EZ pts were found to have incidental grade 1 asymptomatic fracture at the site of bone metastasis on routine imaging, at 15 and 31 months respectively after the last dose of RA, and did not require any intervention. No patients developed bone marrow disorders during the follow-up period. Efficacy and safety data will be elaborated during the meeting. Conclusions: In our study, EZ+RA resulted in significant long-term clinical benefit over EZ alone in pts with mCRPC without compromising safety. * NA&amp;BLM; equal contribution. Clinical trial information: NCT02199197. [Table: see text]

Evolving Role of Immunotherapy in Metastatic Castration Refractory Prostate Cancer.

Immunotherapies have shown remarkable success in the treatment of multiple cancer types; however, despite encouraging preclinical activity, registration trials of immunotherapy in prostate cancer have largely been unsuccessful. Sipuleucel-T remains the only approved immunotherapy for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer based on modest improvement in overall survival. This immune evasion in the case of prostate cancer has been attributed to tumor-intrinsic factors, an immunosuppressive tumor microenvironment, and host factors, which ultimately make it an inert ‘cold’ tumor. Recently, multiple approaches have been investigated to turn prostate cancer into a ‘hot’ tumor. Antibodies directed against programmed cell death protein 1 have a tumor agnostic approval for a small minority of patients with microsatellite instability-high or mismatch repair-deficient metastatic prostate cancer. Herein, we present an overview of the current immunotherapy landscape in metastatic castration-resistant prostate cancer with a focus on immune checkpoint inhibitors. We describe the results of clinical trials of immune checkpoint inhibitors in patients with metastatic castration-resistant prostate cancer; either as single agents or in combination with other checkpoint inhibitors, poly (ADP-ribose) polymerase (PARP) inhibitors, tyrosine kinase inhibitors, novel hormonal therapies, chemotherapies, and radioligands. Finally, we review upcoming immunotherapies, including novel monoclonal antibodies, chimeric-antigen receptor (CAR) T cells, Bi-Specific T cell Engagers (BiTEs), therapies targeting the adenosine pathway, and other miscellaneous agents.

Metastasis-directed therapy in castration-refractory prostate cancer (MEDCARE): a non-randomized phase 2 trial

BackgroundPatients diagnosed with metastatic castration-refractory prostate cancer (mCRPC) rely on a limited number of therapeutic agents resulting in a median survival of 2–3 years. A subgroup of those patients with mCRPC presents with oligoprogressive disease, with a limited number of progressive lesions while other metastases are still controlled by ongoing systemic treatment.MethodsIn this single arm prospective phase II trial, we aim to include 18 patients with oligoprogressive mCRPC (1–3 metastases and/or local recurrence) who will be treated with metastasis-directed therapy to all visible progressive lesions. Progression is based on conventional imaging, as the use of PSMA PET-CT is considered investigational. However all patients will undergo PSMA PET-CT and the images will be blinded until progression. Primary endpoint is the postponement of the start of next-line systemic treatment (NEST) and the additional clinical value of PSMA PET-CT. Recruitment of patients for this trial started in January 2020 and will be completed approximately by December 2020.DiscussionIn this phase 2 trial on oligoprogressive mCRPC, we will investigate the benefit of progression-directed therapy while continuing ongoing systemic treatment. We hypothesize that progression-directed therapy (PDT) with surgery or stereotactic body radiation therapy for these oligoprogressive lesions will postpone the start of next-line systemic treatment and therefore serve as a new or add-on therapy in the spectrum of treatments available for mCRPC. The results of this trial will serve as guidance for a later randomized phase 3 trial. All participants are given an information sheet and are required to give written informed consent. Results will be published in a peer-reviewed journal.Trial registrationThis study is registered at ClinicalTrials.gov: NCT04222634 (December 18th 2019).

Randomized phase II trial of radium-223 (RA) plus enzalutamide (EZ) versus EZ alone in metastatic castration-refractory prostate cancer (mCRPC): Long-term follow up of secondary endpoints.

125 Background: RA, a bone targeting alpha radiopharmaceutical, and EZ, are approved for mCRPC. Per phase 3 SWOG0421 trial, men with mCRPC and a significant decline in serum bone metabolism markers (BMM) had improved survival with atrasentan, a bone targeting agent (PMID 24565955). We hypothesized that RA+EZ is safe, and decrease bone metabolism markers compared to EZ alone. Here we report the long-term follow up of the secondary clinical endpoints. Methods: In this phase 2 trial (NCT02199197), men with progressive mCRPC were treated with EZ (160 mg daily) ± RA (standard dose of 55 kBq/kg IV Q4 weeks x 6), until disease progression or unacceptable toxicities. Primary objectives: 1) changes in N-telopeptide compared from baseline to end of treatment; 2) safety. Secondary objectives: changes in 4 other markers of bone resorption or formation, and PSA progression free survival (PSA-PFS), radiographic PFS (rPFS) and overall survival (OS). Results: After a safety lead in phase (n=8), 39 men were randomized (2:1) to RA+EZ vs EZ. Median follow up is 19.3 months (range 3 – 24 months). Combining RA+EZ was safe (2018 ASCO annual meeting abstract: 5057) and met the primary endpoint (2018 ESMO annual meeting: Annals of Oncology). There was a consistent trend regarding PSA-PFS, rPFS and OS favoring RA+EZ over EZ. . . (Table). Notably, no bone fractures have occurred in either group with extended follow up. Conclusions: The use of RA+EZ was safe with a longer follow up with no increase in skeletal related events including fractures. All secondary endpoints, numerically favored RA+EZ vs EZ. Clinical trial information: NCT02614859.

Possibilities of treatment of patients with castrationrefractory prostate cancer using enzalutamide

Prostate cancer is one of the most actual oncourological diseases because of the persisting high rates of morbidity and mortality from this pathology. More than 1 100 000 new cases of this pathology are registered in the world every year. The incidence of prostate cancer in the Russian Federation continues to increase steadily. Despite the success in early detection of this disease, primarily due to the introduction of diagnostics with the use of a specific prostatic antigen, the frequency of detection of primary metastatic cancer of the prostate gland remains high and is about 20%. Metastatic castration-resistant prostate cancer is an extremely heterogeneous disease with an unfavorable prognosis in most of these patients, which requires a differentiated approach when prescribing therapy in each case. Despite the standard approach to prescribing chemotherapy as one of the main methods of drug treatment, the method of hormonal therapy of the second line using drugs aimed at the androgenic mechanism of cellular proliferation regulation is an effective and less toxic option. A fundamentally different mechanism of action has a new drug hormonal therapy of the second line enzalutamide, which is able to selectively block androgen receptors and disturb the translocation of the signal from the receptor into the cell and the cell nucleus. A number of large randomized trials that studied the effectiveness of this drug have allowed to register it for clinical use, including in our country. The article presents a review of the literature on the use of enzalutamide in patients with metastatic castration-refractory prostate cancer, as well as a description of the clinical case of the use of this drug in real practice.

Progression-directed Therapy for Oligoprogression in Castration-refractory Prostate Cancer

In metastatic castration-refractory prostate cancer (mCRPC), state-of-the-art treatment consists of androgen biosynthesis inhibition (abiraterone), inhibition of the androgen receptor (enzalutamide), chemotherapy, or radium-223 in combination with androgen deprivation therapy (ADT). A subgroup of these patients show oligoprogression, with the progression of only a limited number of metastatic spots, while all other metastases remain controlled by ongoing systemic therapy. In a bi-institutional retrospective study, we tested the hypothesis that progression-directed therapy (PDT) targeting oligoprogressive lesions might defer the initiation of next-line systemic treatment (NEST). A total of 30 patients were diagnosed with mCRPC and experienced oligoprogression, defined as a total of three or fewer progressive lesions either at known metastatic sites and/or the appearance of new metastasis and/or local recurrence. All patients were under active ADT with or without second-line systemic treatment. All patients received PDT targeting the oligoprogressive lesions, while ongoing systemic treatment was maintained. There was median NEST-free survival of 16mo (95% confidence interval [CI] 10–22) and progression-free survival of 10mo (95% CI 6–15) with only minor radiotherapy- or surgery-related toxicity. These findings encourage further prospective trials. Patient summaryIn patients with metastatic castration-refractory prostate cancer, surgical treatment or high-dose radiation therapy directed to only the limited number of progressive metastatic spots, while all other metastases remained controlled by ongoing systemic therapy, led to substantial postponement of next-line systemic treatment in our study.

Genomic landscape of metastatic hormone sensitive prostate cancer (mHSPC) vs. metastatic castration-refractory prostate cancer (mCRPC) by circulating tumor DNA (ctDNA).

5043 Background: mCRPC carries a poor prognosis, and targeted therapies have had minimal success in mCRPC. Novel genomic targets could improve drug development. To date, large ctDNA studies in metastatic prostate cancer have been descriptive with limited or no clinical annotation. Herein, we hypothesize that profiles of genomic alterations (GAs) in ctDNA not only differ significantly between, but can also be used to predict mCRPC vs. mHSPC. These findings could help identify new drug targets for mCRPC treatment. Methods: Men with mHSPC or mCRPC who underwent NGS of ctDNA using G360 (Guardant Health Inc.) at the Huntsman Cancer Institute were included. Men were classified as mCRPC or mHSPC (patients with current or no prior ADT). G360 detects somatic mutations in selected exons of 73 genes, amplifications in 18 genes, and selected fusions in 6 genes. Two-sided students t-test was used to compare the %cfDNA and total GAs. The Chi squared test was used to compare the frequency of each GA. Machine learning (ML) algorithms were trained on GAs and benchmarked by cross-validated performance. GAs contributing to mCRPC vs. mHSPC classification were measured by ML feature importance (e.g. odds ratios, regression coefficients). Results: Of the 259 men included, 119 men had mHSPC and 140 had mCRPC. Men with mCRPC had more GAs (4.5 vs. 1.86, p&lt;0.0001) and higher %cfDNA (9.56% vs. 5.02%, p=0.02). In mHSPC, there was no significant difference in the number of GAs or %cfDNA between men on ADT and those who hadn’t yet started ADT. ML algorithms used GAs to predict mCRPC with 78.1% sensitivity, 64.0% specificity, 76.7% PPV, 65.1% NPV, and 70.3% overall accuracy. mCRPC was enriched with GAs in AR, ARID1A, BRAF, BRCA2, CCNE1, CTNNB1, EGFR, FGFR1, KIT, MET, MYC, PDGFRB, PIK3CA, and TP53. Of note, many of these genes are involved in MAP/ERK signaling. Conclusions: Men with mCRPC have more GAs, higher %cfDNA, and enrichment of GAs in the MAP/ERK pathway compared to men with mHSPC. The distinct GAs seen in mCRPC represent novel therapeutic targets, especially in the MAP/ERK pathway. We also show that machine learning can differentiate mHSPC and mCRPC based on GAs detected in ctDNA.

825P - Randomized phase II trial of radium-223 (RA) plus enzalutamide (EZ) vs. EZ alone in metastatic castration refractory prostate cancer (mCRPC)

825P - Randomized phase II trial of radium-223 (RA) plus enzalutamide (EZ) vs. EZ alone in metastatic castration refractory prostate cancer (mCRPC)

Safety data from a phase II randomized trial of radium-223 dichloride (Ra-223) plus enzalutamide (Enza) vs. Enza alone in men with metastatic castration refractory prostate cancer (mCRPC).

5057Background: Ra-233, a bone targeting alpha radiopharmaceutical, and Enza, are approved for mCRPC. Per SWOG0421, the subset of men with mCRPC with the highest bone metabolism marker levels had i...

AR-V7 Androgen Receptor Variant as a Predictor of Response to Androgen-receptor Targeting Agents Used to Treat Castration-refractory Metastatic Prostate Cancer

Several systemic treatment options are currently available for patients with metastatic castration-refractory prostate cancer (mCRPC), including the androgen-receptor targeting agents (ARTA) enzalutamide and abiraterone, the taxanes docetaxel and cabazitaxel, and the radioisotope drug 223-radium dichloride. In some patients with mCRCP, alternative splicing of androgen receptor (AR) mRNA occurs, resulting in the formation of a truncated AR lacking the androgen-binding domain. These receptors activate downstream signalling pathways even without the ligand. Recent studies show that the presence of the AR-V7 (ARV - AR variants) splicing variant is associated with resistance to ARTA. Bec>ause the presence of AR-V7 does not affect the efficacy of other systemic therapies used in mCRCPs, particularly taxanes, AR-V7 is a candidate predictive biomarker for the individualisation of mCRCP treatment. Two types of assays based on mRNA or abnormal protein detection are used to detect AR-V7 in circulating tumour cells. To describe the current status of AR-V7 testing in mCRPC and possible applications of this method for predicting outcomes of ARTA therapy. The percentage of CTC AR-V7+ in ARTA-naive men is relatively low at baseline, but in patients pretreated with ARTA, the prevalence of AR-V7 increases to 19-34%. Given the relatively high expected prevalence, AR-V7 testing may be economically feasible in this population. The proportion of AR-V7+ patients responding to ARTA retreatment appears to be very low, at only 4.8%. AR-V7 testing could thus be useful if an ARTA switch is considered in a patient progressing onto an ARTA drug. Both protein-based tests and mRNA-based tests are currently undergoing clinical validation in prospective studies, with results expected within a year.Key words: prostate cancer - abiraterone - enzalutamide - alternative splicing - drug resistanceSubmitted: 30. 8. 2017Accepted: 5. 11. 2017 doc. MUDr. Tomáš Büchler, Ph.D. received honorary lectures and publications from Astellas and Janssen and a travel grant from Janssen. Supported by Ministry of Health, Czech Republic - conceptual development of research organization Thomayer Hospital - TN 0064190. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.