Bone Mets Research Articles

Deferring Treatment in Men With Low and Low-Intermediate Risk Prostate Cancer Does Not Adversely Affect Outcome

Deferring treatment in men who present with low and low intermediate risk prostate cancer is actively championed as a appropriate care for this group of patients. However it is often difficult for a patient to reconcile the idea of doing nothing when told they have cancer and advertisements for safe noninvasive treatment assail them on every front. This study attempts to provide data on long term follow up of a group who did not immediately choose treatment. Between 2000 and 2015, 2437 men were diagnosed with prostate cancer in a VA Healthcare facility. Eleven percent or 274 patients elected a course of watchful waiting or active surveillance. Thirty three percent or 89 of these men deferred treatment for more than 12 months and then elected to pursue treatment. We reviewed the reasons for selecting treatment and as well as the results of treatment. The majority of patients (95.5%). were Gleason’s 6 (70%) or 7 (25%) The median duration for deferring treatment in the Gleason 6 cohort was 31 months and for the Gleason 7 group it was 19 months. Eighty men (94%) eventually received curative therapy; surgery or radiation +/-hormonal therapy or hormonal therapy alone.Five men consistently refused treatment and ultimately started hormonal therapy when diagnosed with bone mets and survived between 9.5 and 14 years. The reasons why patients chose to start treatment in the Gleason 6 group were: increasing Gleason’s score on rebiopsy (22), increasing PSA (16), physician’s advice (16) personal choice (6) metastatic disease (4) and other(4). Three of the 4 men starting for mets had PSA values >100ng/ml. In the Gleason 7 group the reasons were similar: Increased PSA (9), increasing Gleasons score on rebiopsy (5), physician’s advice (4) personal choice (3) metastatic disease (1). The patients treated for curative intent have a median follow up of 50 months (3-84 months) in the Gleason 6 group and 60 months (7-166 months) in the Gleason 7 group. The survival since diagnosis ranges from 26 to 273 months for the Gleason 6 patients ( median 67 months) and 29 to 180 months for the Gleason 7 patients, (median 78 months). Of the 80 patients, 54 are bNED, 17 are cNED, 6 are AWD, 2 DWD and I DOD. Among men who elected only hormonal therapy the median follow since diagnosis up is 154 months for Gleason 6 and 94 months for Gleason 7. Also only 4 patients actually died of disease and 3 of these were in the group who chose no treatment until they developed bone mets. With only 4 relapses and 1 death among the 85 Gleason 6 and 7 tumors, a 100% survival would fall within the 95% confidence interval. Men with Gleason score 6 tumors and low-intermediate risk Gleason 7 tumors may defer treatment with active surveillance and follow-up biopsies without compromising their prostate cancer specific survival. This has important implications for assessing the risks vs. benefits of prostate cancer screening programs.

Palliating Bone Mets at the End of Life: Are We Choosing Wisely?

Palliating Bone Mets at the End of Life: Are We Choosing Wisely?

887P - Negative prognostic factors and resulting clinical outcome in patients (pts) with metastatic renal cell carcinoma (mRCC) included in the Italian nivolumab expanded access program (EAP)

Background: In recent years, prognostic classifications have been considered an area of growing interest in mRCC. However, independently from the classification used (Memorial Sloan Kettering versus Heng’s) the presence of brain, liver and bone metastases (mets) or sarcomatoid features (G4) resulted in a poorer outcome for pts with mRCC treated with targeted therapies (antiangiogenic agents or mTOR Inhibitors). Regarding this topic, the large Italian EAP represent an important opportunity to analyze the impact of nivolumab in pts treated in a daily clinical practice setting. Methods: Nivolumab was available upon physician request for pts aged ≥18 years who relapsed after at least one prior systemic treatment in the advanced or metastatic setting. Nivolumab 3 mg/kg was administered intravenously every 2 weeks for a maximum of 24 months. Pts included in the analysis had received ≥ 1 dose of nivolumab and were monitored for adverse events (AEs) using Common Terminology Criteria for Adverse Events. Results: Of 389 Italian pts with mRCC enrolled in the EAP, 32 pts (8%) had brain mets, 128 (33%) had liver and 193 (50%) had bone mets. Baseline characteristic are described in the Table. These pts achieved a disease control rate (DCR) of 53%, 45% and 47% respectively. Six and 12 months overall survival rates in the 3 groups of mets were 87.0% and 66.8%, 75.6% and 62.0%, 78.0% and 58.9%, respectively. Histological grading, a matter of high interest, was assigned according to Fuhrman's classification: 51 pts had G4 tumor. The objective response rates in these pts and in the overall population were 23% and 22%, respectively, with a 6 and 12 months OS rate of 61% and 53.6% for the G4 group. The safety profile of the subgroups described above was in line with the general population.Table887PAge, median (range)Brain MetsLiver MetsBone Mets65 (43-77)65 (43-81)65 (40-84)Male %727079ECOG PS %:0 1 2 NA41 50 6 342 50 7 139 48 10 3Number of prior Therapies %:1 2 3 > =4 NA13 44 37 6 013 37 24 24 214 36 30 19 1 Open table in a new tab Conclusions: These results suggest that also pts with poor prognostic factors may derive relevant benefits with nivolumab, with safety results consistent with previously reported data. Clinical trial identification: Expanded Access Program Legal entity responsible for the study: Italian RCC EAP Group Funding: None Disclosure: S. Bracarda: Advisory Board Member for Pfizer, Novartis, Bristol-Myers Squib, Exelixis, Ipsen, Roche, Genentech, Eusa Pharma. PI for clinical studies with Bristol-Myers Squib, Pfizer, Roche, Exelixis. L. Galli: Advisory Board for Pfizer, Novartis. U. De Giorgi: Advisory Board for Bristol-Myers Squib, Pfizer, Novartis, Ipsen, Astellas, Janssen, Sanofi. G. Procopio, C. Porta: Advisory Board for Bristol-Myers Squib, Pfizer, Novartis, Ipsen. E. Cortesi: Advisory Board for Bristol-Myers Squib, Pfizer, Ipsen. All other authors have declared no conflicts of interest.

Abstract CT031: A phase Ib trial to study the safety and tolerability of atezolizumab with radium-223 dichloride in patients with metastatic castrate-resistant prostate cancer (mCRPC)

Abstract Background: In patients (pts) with mCRPC, bone metastases (mets) occur up to 80% of the time and are a significant cause of morbidity and mortality. Radium-223 dichloride (Ra-223) is a targeted α-emitter and extends overall survival (OS) in mCRPC pts with symptomatic bone mets. While several therapies, including Ra-223, have recently been approved for mCRPC, pts ultimately develop resistance and progressive disease. Therefore, there is a high unmet need for new treatments for mCRPC pts. Atezolizumab (atezo) is a humanized mAb that targets PD-L1 and blocks its interaction with its receptors, PD-1 and B7.1, which is expected to enhance T-cell responses and improve anti-tumor activity. A pre-clinical study found that tumor and dendritic cells have higher PD-L1 expression after ionizing radiation (IR) exposure and that combining anti-PD-L1 therapy with IR enhanced the inhibition of tumor growth. Radiotherapy leads to immune modulation and may help prime an immune response by releasing tumor-associated antigens that may target tumors distant from the local radiation field (i.e., abscopal effect). These data support the hypothesis that atezo + Ra-223 may be an effective therapy for CRPC pts with bone and soft tissue mets. Methods: A phase Ib clinical trial (NCT02814669) is being conducted to assess the safety and tolerability of atezo + Ra-223 in pts with mCRPC after progression on an androgen pathway inhibitor and to identify a recommended treatment schedule. Pts will have mCRPC with at least 2 bone mets and either measurable visceral (non-liver) mets or lymphadenopathy. Eligibility criteria include ECOG PS 0-1, progression on an androgen pathway inhibitor, and soft tissue disease amenable for serial biopsy. Exclusion criteria include small cell or neuroendocrine prostate cancer, autoimmune disease, eligible for and willing to receive treatment with taxanes, and prior treatment with Ra-223. Pts will receive atezo (840 mg q2w) and Ra-223 (55 kBq/kg q4w). The study includes a cohort phase, to evaluate a concurrent dosing regimen, and if safe and tolerable, a randomization phase to compare concurrent and staggered dosing. Regimens that are safe and tolerable may undergo expanded enrollment. A recommended schedule will be based on incidence of dose-limiting toxicities during first cycle of combination treatment. A preliminary assessment of efficacy will include ORR per RECIST v1.1, DOR, rPFS, OS, and PSA response rate. Approximately 45 pts will initially be enrolled in the United States. Citation Format: Lawrence Fong, Michael Morris, Andrew Armstrong, Daniel Petrylak, Ulka Vaishampayan, Ajjai Alva, Jean Hoffman-Censits, Indrani Sarkar, Susheela Carroll, Christina Schiff, Oliver Sartor. A phase Ib trial to study the safety and tolerability of atezolizumab with radium-223 dichloride in patients with metastatic castrate-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT031. doi:10.1158/1538-7445.AM2017-CT031

Phase 2 biomarker-driven study of ipilimumab plus nivolumab (Ipi/Nivo) for ARV7-positive metastatic castrate-resistant prostate cancer (mCRPC).

5035 Background: ARV7+ mCRPC is an aggressive phenotype with a median PFS of 3-4 mo and OS of 7-9 mo. We hypothesized that ARV7+ tumors would be enriched for DNA repair mutations, rendering them more responsive to combined immune checkpoint blockade. Methods: We enrolled 15 mCRPC pts with ARV7+ CTCs (using a CLIA-certified assay) into a single arm phase 2 study. Pts received Nivo 3 mg/kg plus Ipi 1 mg/kg every 3 wk x 4 doses, then maintenance Nivo 3 mg/kg every 2 wk. Targeted sequencing for DNA repair defects was performed on pretreatment tumor biopsies (n=11) or cell-free DNA (n=4). Primary endpoint: PSA50response rate. Secondary endpoints: objective response rate (ORR) in pts with measurable disease, durable PFS (lack of progression ≥24 wk), PSA‐PFS, radiographic (r)PFS, overall survival (OS), and frequency/intensity of AEs. Results: 15 ARV7+ men were enrolled, with median f/u 8.4 (range 1.9–10.5) mo. Median age was 65, 47% had ECOG ≥1, median PSA was 115 ng/mL, 67% had visceral/nodal mets, all had bone mets, and 60% had ≥4 prior regimens for mCRPC. Mean ARV7/AR ratio was 23% (range 3–75%). 6/15 men (40%) had pathogenic DNA repair gene mutations ( BRCA2, ATM, MSH6, FANCM, FANCA, POLH). Overall, the PSA50rate was 1/15 (7%), ORR was 2/8 (25%), durable PFS rate was 3/15 (20%), PSA-PFS was 3.0 (95%CI 2.1–4.9) mo, rPFS was 3.9 (95%CI 2.8–5.5) mo, and OS was 9.5 (95%CI 7.2–NA) mo. Outcomes appeared better in DNA repair deficient (DRD+) tumors vs. DNA repair proficient (DRD–) tumors (TABLE). 15 grade 3-4 treatment-related AEs occurred in 7/15 (46%) men (including 2 hepatitis, 2 colitis, 1 pneumonitis); there were no treatment-related deaths. Conclusions: In this first study targeting ARV7+ mCRPC, treatment with Ipi/Nivo had acceptable safety and encouraging efficacy, particularly in men with DRD+ tumors. DNA repair mutations may be enriched in ARV7+ prostate cancer. Clinical trial information: NCT02601014. [Table: see text]

Clinical correlates of response to anti-PD-1 (aPD1)-based therapy in patients (pts) with metastatic melanoma (MM).

e21000 Background: aPD1, alone or in combination with ipilimumab (IPI), produces durable responses in a subset of MM. Tumor features that correlate with treatment response, including size, number, and location of metastases (mets) are not well defined. Methods: We collected clinical data from mm pts treated at one center who received aPD1 (n = 185) or aPD1 + IPI (n = 42). We correlated number of mets, size of largest tumor, and organ involvement with response rate (RR), progression-free survival (PFS) and overall survival (OS). Results: Among all pts, RR was 67% for aPD1 + IPI and 41% for aPD1 alone. In univariate analyses, responders to aPD1 had lower diameter of largest tumor (4cm vs. 5.5cm; p = 0.02) whereas aPD1 + IPI had equivalent largest tumor diameters (p = 0.65). Regarding sites of mets, liver mets were associated with lower RR in aPD1 treated pts (26% vs. 46%), lower PFS (median 138 vs. 326 days, p = 0.02), and lower OS (median 334 vs. 1080 days, p < 0.01). No associations with RR, PFS, or OS were observed with liver mets in aPD1 + IPI treated pts. We also did not observe any differences between pts who did or did not have lung, lymph node, or brain mets for either aPD1 or aPD1 + IPI. Interestingly, superior RR to aPD1 + IPI was observed in pts with bone mets compared to those without bone mets (91% vs. 58%, p = 0.048). Regarding number of sites, RR to aPD1 was greater in pts with ≤10 mets compared with those with > 10 (46% vs. 28%, p = 0.02), although no consistent relationship was observed at lower cutoffs. In multivariable analyses, diameter of largest tumor (tumor bulk) was independently associated with PFS (OR, 1.11, p < 0.001) and OS (OR 1.08, p < 0.001) whereas AJCC stage, lactate dehydrogenase, liver mets, ECOG performance status, number of mets, and prior therapies were not significant. Tumor bulk and other risk factors were not associated with PFS or OS in aPD1 + IPI. Conclusions: Tumor bulk was strongly and independently associated with clinical outcomes in aPD1 but not IPI + aPD1. Other associations with disease sites (liver and bone) need further validation. In conjunction with molecular biomarkers, clinical predictors may help guide selection of aPD1 or aPD1 + IPI.

Prognostic value of neutrophil-to-lymphocyte ratio (NLR) in metastatic castration-resistant prostate cancer (mCRPC) pts receiving a new agent (NA)- based third line treatment: Final results from a multicenter Italian study.

e16521 Background: High NLR has been reported to be a poor prognostic indicator in both first and second mCRPC lines, while no information is available concerning this issue in pts treated in third line therapy. The present study is aimed to assess the possible relationship between third line clinical outcomes and NLR in a series of mCRPC pts treated with a NA [abiraterone acetate (AA), cabazitaxel (CABA), or enzalutamide (ENZ)] after the failure of docetaxel (DOC) and another NA. Methods: We collected data of pts who received sequentially two NAs after DOC in 38 Italian hospitals. For each pt we recorded the clinical outcome of all treatments received after DOC. Cox regression analysis was used to assess the independent prognostic value of a series of pretreatment covariates, in terms of overall survival (OS), comprising NLR. Results: A consecutive series of 476 mCRPC pts with bone (86%), nodal (56%) or visceral (15%) mets, was collected. All pts received a NA-based third line: 135 received AA, 221 CABA and 120 ENZ. Data on NLR were available for 398 pts (84%). In the univariate analyses, the NLR as a discrete variable dichotomized according to the Maximally Selected Log-Rank statistics (optimal cut-off: 3.66), was significantly associated with both OS and progression free survival (PFS), calculated from the third line start (p < 0.0001). At the multivariate analysis, NLR, performance status, pain, hemoglobin, alkaline phosphatase, treatment with AA and with CABA were independent prognostic factors for PFS, while NLR, performance status, hemoglobin, PSA, and lactate dehydrogenase were independent prognostic factors for OS. In Kaplan-Meier analysis, the median OS from the start of third-line was higher (14.2 vs 9.3 mos) in pts with NLR ≤ 3.1 compared to those with NLR > 3.1 (log-rank; P < 0.0001). Similarly, the median PFS was 5.5 and 3.8 (log-rank; P < 0.0001) in pts with NLR ≤ 3.66 and > 3.66, respectively. Conclusions: Our results, observed in the largest cohort of mCRCP pts treated with NA-based third line after DOC and another NA, confirms that NLR is an independent factor for PFS and OS also in this population.

Phase II study of individualized sunitinib (SUN) as first-line therapy for metastatic renal cell cancer.

4514 Background: Higher SUN exposure is associated with better outcomes. Patients (pts) with minimum toxicity on the standard schedule do worse than pts needing dosing changes for toxicity. Methods: It was hypothesized that toxicity-driven dose/schedule individualization would improve the primary endpoint (PFS) from 8.5 (EFFECT trial) to 14 months (mo), with 99 pts required to detect this with 90% power and 2-sided alpha = 0.05. In a prospective phase II study (eligibility as EFFECT) pts start on 50 mg/day (d) for 28 d with treatment (Rx) breaks reduced to 7 d. If grade-2 toxicity develops before d 28, pts stay on a 50 mg on the next cycle with the number of d on Rx individualized aiming for ≤ grade-2 toxicity. Dose is reduced to 37.5 mg and then 25 mg if pts do not tolerate a 50 mg or 37.5 mg dose respectively for at least 7 d. Pts with minimum toxicity on d 28 are escalated to 62.5 mg and then 75 mg. Results: 117 pts were enrolled in 12 centers. Nine non-evaluable pts came off early due to toxicity (5), non-compliance (2) and global deterioration (2). Of 108 pts evaluable for response (IMDC favorable 31.5%, intermediate 58.3%, poor 10.2%. Bone mets 19%, Nephrect 83%), 10 are still on Rx. Dose was escalated in 20 pts (18.5%) to 62.5 mg (12 pts) and then to 75 mg (8 pts). In 49 pts (45.4%) eligible for dose reduction by standard criteria, a 50 mg dose was maintained but for 7 - 24 d, while 7 pts (6.5%) stayed on a 28 d schedule. Dose was reduced to 37.5 mg in 22 pts (20.4% vs. 36 - 63% in 4 large SUN trials) and to 25 mg in 10 pts (9.3% vs. 27 - 43% in 4 trials). Rx was stopped due to toxicity in 10/117 pts (9.3% vs. 15 - 19% in 4 trials). See table for response (ORR, 108 pts) and survival (117 pts) data vs. EFFECT (146 pts). The median followup is 15.5 mo (0.6 -37.9) for PFS and 24.5 mo (4.4 - 47.7) for OS. Conclusions: The null hypothesis of the PFS being 8.5 mo can be rejected with a p < 0.001. Individualized dosing is safe and feasible in a multicenter setting and associated with improved dose intensity and one of the best ORR, PFS and OS reported for a TKI. Clinical trial information: NCT01499121. [Table: see text]

P14.03 Meninges metastases in breast cancer-one center study experience of concomitant therapy intrathecal and systemic

Breast cancer occupies the central nervous system frequently. The treatment is controversial. Therapeutic recommendations depend on the patient’s condition,suggesting only palliative care, or radiotherapy or intrathecal therapy, the systemic therapy on a trial basis.There are different forms of the meninges infiltration: meningitis with the cancer cells in the cerebrospinal fluid or the solid infiltrates, only as enlargment or classical metastases to the meninges. Currently the base of the diagnose is a result of the MR and the clinical symptoms; positive cerebrospinal fluid analysis is not required. Classical meningitis lasts 4 to 11 weeks, while the solid leasion is a chronic disease and can last for many months. We present one-center study experience of concomitant therapy:intrathecal and systemic in the group of patients, in which the spread to meninges was proven without the classical meningitis symptoms. Material: from 2007 to 2015 27 patients with confirmed spread were treated. Overexpression of HER 2 (9 patients) and triple negative (5 patients coexisted with brain metastases, while the luminal B1/A (13 patients) with the bone mets. Except of one case, it was always a multi-organ disease. METHODS:We used liposomal cytarabine. We plan to give 6 intrathecal injections every 14 days, the systhemic therapy depends on the biological subtype and on the former used drugs. We applied: Liposomal doxorubicine (10 patients), Fulvestrant / Aromataze inhibitor (8 patients),Cisplatine (4 patients),Paclitaksel (3 patients) and Lapatinib with Capecytabine (2 patients). The response to treatment was monitored by clinical evaluation and MR. Results: the period between the original diagnose to meninges recurrence took in average 41,3 months. No relation between the frequency of occurence of the meningitis and the subtype of breast cancer was found. . Time to progression was between 2,9 - 189 months. The median survival time is 5,8 months. The longlasting survival of 189 months concerns a patient with luminal B1 subtype.We used liposomal cytarabine injections 73 times, in average 3 injections.. Reason of all premature withdraw was deterioration of patient’s condition. There was no case of withdrawing due to any advers events. The biggest clinical benefit was observed in case of the patients who were treated with Lapatinib and Capecitabine - OS 11-12 months; and those treated with hormonal therapy -OS 6-10 months. An objective response,monitored by MR was confirmed in the group of patients treated with Lapatinib (2 patients) and of those treated with Cisplatine (4 patients). CONCLUSION: The course of the disease depends on the breast cancer’s biological subtype and the efficiency of the applied systemic therapy. The intrathecal therapy should be used as one of the elements of the whole treatment. The combined therapy is well tolerated by patients.

Assessing bone response to cabozantinib in patients (pts) with metastatic urothelial carcinoma (mUC) using 18F-Sodium Fluoride (NaF) PET/CT.

328 Background: NaF PET/CT is a radiotracer used for the assessment of bone metastases (mets). The goal of our study was to assess bone mets using NaF PET/CT imaging in mUC pts treated with cabozantinib. Methods: We conducted a single-arm phase II trial of cabozantinib in pts with mUC. Pts with known bone mets underwent a NaF PET/CT scan at baseline and every 8 weeks until progression. At each scan, we captured, the number of lesions per pt and per anatomical site, the maximum standardized uptake values (SUV), and serum alkaline phosphatase (AP). Bone responses (bone response (BR), stable disease (SD), progressive disease (PD)) were assigned to each pt based on the NaF report. Change from baseline to the time of best response for SUV, the number of lesions, and AP were compared between BR + SD vs PD were analyzed using an exact Wilcoxon rank sum test. The Kaplan-Meier method was used to determine the association of progression free survival (PFS) or overall survival (OS) with baseline SUV and number of lesions. Results: 68 pts enrolled on study, 22 pts had bone mets at baseline (6 bone only and 16 with bone and soft-tissue mets) (median OS 4.6 mo (95% CI: 3.4-7.7 mo), and median PFS 2.0 mo (95% CI: 1.8-3.9 mo)) of which 15 pts had follow up NaF scans. At baseline, 147 total lesions were analyzed, and the lesion distribution was: spine 29%, ribs 21%, pelvis 18%, skull 11%, femur 6%, scapula 3%, humerus 3%, sternum 3%, sacrum 3%, fibula 1%, and clavicle 0.7%. 5/15 pts had BR (and remained on study 238, 252, 182, 161, and 56 days), 4/15 SD, and 6/15 PD at best response. Sites of PD occurred in bone 10/22, bone and soft-tissue 5/22, and soft-tissue 7/22. The percent difference in number of lesions among responders and non-responders was 43% (p = 0.0039). At baseline, there was no association with PFS or OS and number of lesions (p = 0.84, p = 0.97), SUV (p = 0.83, p = 0.97), or AP (p = 0.97, p = 0.33). Conclusions: Pts with mUC and bone disease have poor overall outcome. Most bone lesions were found in the spine, ribs, and pelvis. Larger studies are needed to assess the correlation of NaF response with clinical outcome in mUC. We have an ongoing study using NaF PET to assess bone mets in mUC treated with cabozantinib/nivolumab/ipilimumab. Clinical trial information: NCT01688999.

Patients with metastatic castration-resistant prostate cancer (mCRPC) are primary resistant (PR) to the new agent (NA)-based second line: Clinical outcomes and prognostic factors of subsequent treatment with another NA.

e585 Background: Several NA [abiraterone acetate (AA), cabazitaxel (CABA), or enzalutamide (ENZ)] changed the prognosis of mCRPC pts being able to significantly prolong their overall survival (OS) after docetaxel failure. Unfortunately, a quote of pts experiences an early progression (within 3 mos) during the second line treatment and it is unclear if a clinical benefit may result from a subsequent treatment with another NA. The present study is aimed to assess the clinical outcomes and prognostic factors of subsequent NA treatment in those pts PR to the second line NA. Methods: We collected data of pts who received sequentially two NAs after DOC in 38 Italian hospitals. For each pt we recorded the clinical outcome of all treatments received after DOC. For the purpose of the present analysis we consider as PR pts who progressed within 3 months from the start of the NA second line. Cox regression analysis was used to assess the independent prognostic value of a series of third-line baseline covariates, in terms of progression free survival (PFS) and OS. Results: A consecutive series of 476 mCRPC pts with bone (86%), nodal (56%) or visceral (15%) mets, was collected. The NA-based second line consisted of AA (261 pts), CABA (151), and ENZ (64): we identified 55 PR pts (AA 24 – CABA 24 – ENZ 7). All pts received a subsequent NA-based third line: 22 received AA, 25 CABA, and 8 ENZ. Compared to no-PR pts, PR pts showed a lower biochemical response rate (12.2% vs 31.6%; p = 0.005), but no significant differences in terms of objective response rate (17.1% vs 15.2%), PFS (median 3.5 vs 4.7 mos), and OS (median 9.4 vs 12.9 mos). Considering the PR population, at the multivariate analysis , lactate dehydrogenase and PSA were independent prognostic factors for PFS in third line, while hemoglobin, PSA, administration of one NA in fourth line and lactate dehydrogenase were independent prognostic factors for OS. Conclusions: In our experience, NA-based third line is active also in mCRPC PR population and some factors may help in selecting patients with higher probability of achieving a disease control.

Prognostic value of neutrophil-to-lymphocyte ratio (NLR) in pts with metastatic castration-resistant prostate cancer (mCRPC) receiving a new agent (NA)- based third-line treatment: Final results from a multicenter Italian study.

230 Background: High NLR has been reported to be a poor prognostic indicator in both first and second mCRPC lines, while no information is available concerning this issue in pts treated in third line therapy. The present study is aimed to assess the possible relationship between third line clinical outcomes and NLR in a series of mCRPC pts treated with a NA [abiraterone acetate (AA), cabazitaxel (CABA), or enzalutamide (ENZ)] after the failure of docetaxel (DOC) and another NA. Methods: We collected data of pts who received sequentially two NAs after DOC in 38 Italian hospitals. For each pt we recorded the clinical outcome of all treatments received after DOC. Cox regression analysis was used to assess the independent prognostic value of a series of pretreatment covariates, in terms of overall survival (OS), comprising NLR. Results: A consecutive series of 476 mCRPC pts with bone (86%), nodal (56%) or visceral (15%) mets, was collected. All pts received a NA-based third line: 135 received AA, 221 CABA and 120 ENZ. Data on NLR were available for 398 pts (84%). In the univariate analyses, the NLR as a discrete variable dichotomized according to the Maximally Selected Log-Rank statistics (optimal cut-off: 3.66), was significantly associated with both OS and progression free survival (PFS), calculated from the third line start (p < 0.0001). At the multivariate analysis, NLR, performance status, pain, hemoglobin, alkaline phosphatase, treatment with AA and with CABA were independent prognostic factors for PFS, while NLR, performance status, hemoglobin, PSA, and lactate dehydrogenase were independent prognostic factors for OS . In Kaplan-Meier analysis, the median OS from the start of third-line was higher (14.2 vs 9.3 mos) in pts with NLR ≤ 3.1 compared to those with NLR > 3.1 (log-rank; P < 0.0001). Similarly, the median PFS was 5.5 and 3.8 (log-rank; P < 0.0001) in pts with NLR ≤ 3.66 and > 3.66, respectively. Conclusions: Our results, observed in the largest cohort of mCRCP pts treated with NA-based third line after DOC and another NA, confirms that NLR is an independent factor for PFS and OS also in this population.

Abstract OT1-04-04: A phase 2 randomized, double-blind, placebo-controlled trial of endocrine therapy ± radium-223 dichloride in HER2-negative, hormone receptor–positive breast cancer patients with bone metastases

Abstract Background: Bone-metastatic breast cancer (MBC) treatment is limited. In a phase 2a study of bone-dominant MBC patients, radium-223, a first-in-class α emitter with targeted cytotoxic effect on bone metastases (mets), reduced bone biomarker levels with favorable safety (Coleman et al. Breast Cancer Res Treat. 2014). Trial design: This study evaluates efficacy and safety of radium-223 versus placebo (pbo), each + endocrine treatment (ET), in patients with HER2- estrogen receptor+ (ER+)bone-dominant MBC (NCT02258464). Patients receive (1:1) radium-223 50 kBq/kg IV or pbo q 4 wk (6 cycles) + ET + denosumab or bisphosphonates + best supportive care. Stratification is by geographic region (EU/N America vs Asia), number of prior ET lines (1 vs ≥ 2) for MBC, and number of prior skeletal-related events (SREs) (1 vs 2). Eligibility criteria: Eligible patients are pre- or postmenopausal with HER2- ER+ bone-dominant MBC and ≥ 2 bone mets or with soft tissue and/or visceral mets, and 1-2 prior SREs (external beam radiotherapy, pathologic bone fracture, spinal cord compression, orthopedic surgery); they have received ≥ 1 line of ET for MBC and are considered appropriate for further ET. Patients must have evaluable disease (RECIST 1.1), be taking bisphosphonates or denosumab for ≥ 1 month before study treatment, have an ECOG score 0-1, and have adequate hematologic, renal, and liver function. Patients must not have had visceral or brain mets or leptomeningeal disease, or need chemotherapy for MBC, and must not be suitable for everolimus for MBC. Patients are not eligible if they had prior radium-223 treatment or have untreated spinal cord compression. Specific aims: The primary end point is SSE-free survival (SSE-FS). Secondary end points are radiologic progression-free survival; overall survival; times to opioid use, pain progression, and cytotoxic chemotherapy; pain improvement rate; and safety. Patients are assessed for efficacy and safety and are followed to SSE, radiologic progression, death, or withdrawal. Statistical methods: Assuming 1-sided α 0.1, power 90%, ∼ 119 SSE-FS events are needed for analysis. Time-to-event analysis will use a log-rank test, accounting for stratification. Kaplan-Meier estimates and survival curves will be given for each treatment group. Safety analyses will be descriptive. Present and target accrual: Target accrual is ∼ 227. Currently, 40 patients are randomized. Contact Oana Petrenciuc, Bayer HealthCare Pharmaceuticals, oana.petrenciuc@bayer.com, for more information. Citation Format: Coleman RE, Fried G, Petrenciuc O, Sawhney A, Li R, Rugo HS. A phase 2 randomized, double-blind, placebo-controlled trial of endocrine therapy ± radium-223 dichloride in HER2-negative, hormone receptor–positive breast cancer patients with bone metastases [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-04-04.

Abstract OT1-04-05: A phase 2 randomized, double-blind, placebo-controlled trial of radium-223 dichloride with exemestane and everolimus in patients with HER2-negative, hormone receptor–positive breast cancer and bone metastases

Abstract Background: Treatment options for bone-dominant metastatic breast cancer (MBC) are limited. Radium-223, a first-in-class α emitter with a targeted antitumor effect on bone metastases (mets), was well tolerated and reduced bone biomarker levels in a phase 2 study in patients with bone-dominant MBC (Coleman et al. Breast Cancer Res Treat. 2014). In patients with HER2- estrogen receptor+ (ER+) bone-dominant MBC, everolimus + exemestane (EVE+EXE) improved progression-free survival (PFS) versus EXE alone. Radium-223 combined with EVE+EXE may improve outcomes in patients with HER2- ER+ bone-dominant MBC; this trial will evaluate efficacy and safety of radium-223 versus placebo in these patients (NCT02258451). Trial design: Patients are randomized to receive (1:1) radium-223 (50 kBq/kg [55 kBq/kg after National Institute of Standards and Technology update] IV) or placebo × 6 cycles q 4 wk + EXE (25 mg PO q d) + EVE (10 mg PO q d) plus best supportive care. EXE+EVE continues until disease progression or unacceptable toxicity. Stratification is by geographic region (EU/N America vs Asia), prior hormone therapy (1 vs ≥ 2), and presence of visceral disease (yes vs no). Eligibility criteria: Eligible patients are pre- or postmenopausal with HER2- ER+ MBC and have ≥ 2 bone mets or have soft tissue and/or visceral mets. Patients must have measurable disease per RECIST v1.1, ≥ 1 prior line of hormone therapy for MBC, and 1-2 prior skeletal-related events; be on bisphosphonates or denosumab; and have an ECOG score of 0-1. Patients must have had no past or current need for chemotherapy for MBC, no unresolved spinal cord compression, and no prior EVE treatment. Specific aims: The primary end point is symptomatic skeletal event–free survival (SSE-FS). Secondary end points are overall survival; times to opiate use, pain progression, and cytotoxic chemotherapy; radiologic PFS; and safety. Safety and efficacy are assessed every 4 weeks. Long-term safety is assessed until study termination. Statistical methods: Assuming a 1-sided α of 0.1, 90% power, ∼ 160 SSE-FS events will be required for the analysis. Efficacy will be analyzed by a stratified log-rank test. Safety analysis will be descriptive. Present and target accrual: Estimated enrollment is ∼ 311 patients. Currently, 74 patients are randomized. Contact Oana Petrenciuc, Bayer HealthCare Pharmaceuticals, oana.petrenciuc@bayer.com, for more information. Citation Format: Rugo HS, Drumea KC, Campone M, Barnadas A, Petrenciuc O, Zhang A, Li R, Coleman RE. A phase 2 randomized, double-blind, placebo-controlled trial of radium-223 dichloride with exemestane and everolimus in patients with HER2-negative, hormone receptor–positive breast cancer and bone metastases [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-04-05.

Abstract CT140: Pilot study of “hyperfractionated” anti-prostate specific membrane antigen (PSMA) radioimmunotherapy (177Lu-J591) for progressive metastatic castration-resistant prostate cancer (mCRPC)

Abstract Background: Phase I and II single dose 177Lu?J591 studies have been published demonstrating safety and efficacy in mCRPC. We reported a study of fractionated-double dose 177Lu?J591 (2 doses given 2 weeks apart), demonstrating the ability to administer higher cumulative doses with a dose-response and also equal or less toxicity. As a single-dose, 70 mCi/m2 results in at least 30% declines in 47% with 41% receiving a platelet transfusion. When administered in 2 divided doses, 80 mCi/m2 results in 25% PSA response with 25% transfusion; 90 mCi/m2 results in 59% response with 65% getting transfused. We hypothesize that additional dose-fractionation will allow a higher cumulative dose with less toxicity. Methods: Patients with progressive mCRPC with normal neutrophil and platelet counts were enrolled in a planned 6-patient pilot study. No selection for PSMA expression was performed. 177Lu-J591 was administered at 25 mCi/m2 every 2 weeks until the emergence of grade 2 myelosuppression. Planar imaging of 177Lu?J591 at 6?8 days following the 1st and 4th doses was performed. Pre- and post-treatment PSA and CTC counts (CellSearch) were measured. Results: 6 men median age 68.5 (range 50-79), PSA 84.8 (14.7-2265), 67% elevated LDH, 83% unfavorable CTC count, 67% prior chemo, all prior exposure to abi/enza. Five (83%) with bone mets, 5 (83%) with lymph node mets, and 2 (33%) with visceral mets. Pts received a range of 3-6 doses (cumulative 75-150 mCi/m2 of 177Lu-J591). Two (33%) had >30% PSA decline and 3 (50%) had CTC count decline. Two (33%) experienced Gr 4 neutropenia (without fever), 3 (50%) had Gr 4 thrombocytopenia, and 2 (33%) had platelet transfusion. Two had worsening cytopenia following partial count recovery during periods of cancer progression, with bone marrow biopsies in both revealing infiltrative tumor without dysplasia. Targeting of 177Lu?J591 at known sites of disease was seen in all (100%) pts. Conclusions: “Hyperfractionation” of radioimmunotherapy with 177Lu?J591 is possible in a heavily pre-treated population with poor prognostic features. Targeted delivery of 177Lu occurs to known sites of disease in an unselected patient population. Study is ongoing to determine the optimal target population and dosing regimen for phase 2 study. Citation Format: Ana M. Molina, Jaspreet S. Batra, Beerinder S. Karir, Yuliya Jhanwar, Shankar Vallabhajosula, Paul J. Christos, Linda Lam, Jennifer Epstein, Irene Karpenko, Himisha Beltran, David M. Nanus, Stanley J. Goldsmith, Neil H. Bander, Scott T. Tagawa. Pilot study of “hyperfractionated” anti-prostate specific membrane antigen (PSMA) radioimmunotherapy (177Lu-J591) for progressive metastatic castration-resistant prostate cancer (mCRPC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT140.

Efficacy of cabozantinib (C) vs everolimus (E) in patients (pts) with advanced renal cell carcinoma (RCC) and bone metastases (mets) from the phase III METEOR study.

4558Background: In pts with metastatic RCC, bone mets are prognostic for poor outcomes and represent an unmet medical need. The Phase 3 METEOR trial (NCT01865747) assessed the efficacy and safety of C vs E in pts with RCC and ≥1 prior VEGFR TKI. The trial met its primary endpoint of improving progression-free survival (PFS; HR 0.58, 95% CI 0.45–0.75; P<0.001) (Choueiri NEJM 2015). As C has shown clinical activity in bone mets in prostate cancer pts (Smith JCO 33 2015 abs 139), we evaluated clinical outcomes in RCC pts with bone mets in METEOR. Methods: 658 pts were randomized (stratified by MSKCC risk group and number of prior VEGFR TKIs) 1:1 to receive C (60 mg qd) or E (10 mg qd). Clinical outcome measures included PFS, ORR, overall survival (OS), and safety. Exploratory endpoints included bone scan response (BSR) in pts with bone scan lesions at baseline (Brown Nucl Med Commun 2012 33:384), incidence of skeletal-related events (SRE), and changes in bone turnover markers. Results: 142 pts had bone mets ...

A phase 2 randomized, double-blind, placebo-controlled trial of endocrine therapy ± radium-223 dichloride (Ra-223) in HER2- hormone receptor+ breast cancer patients with bone metastases.

TPS622Background: Bone-metastatic breast cancer (MBC) treatment (tx) is limited. In a phase 2a study of bone-dominant MBC patients (pts), Ra-223, a first-in-class α emitter with targeted cytotoxic effect on bone metastases (mets), reduced bone biomarker levels with favorable safety (Coleman et al. Breast Cancer Res Treat 2014). This study evaluates efficacy and safety of Ra-223 v placebo (pbo), each + endocrine treatment (ET) in pts with HER2- estrogen receptor (ER)+ bone-dominant MBC (NCT02258464). Methods: Eligible pts are pre- or postmenopausal with HER2- ER+ bone-dominant MBC with ≥ 2 bone mets, soft tissue mets, and 1-2 prior symptomatic skeletal events (SSEs) (external beam radiotherapy, pathologic bone fracture, spinal cord compression, orthopedic surgery) who have received ≥ 1 line ET for MBC and are considered appropriate for further ET. Eligible pts must have evaluable disease (RECIST 1.1), be taking bisphosphonates or denosumab for ≥ 1 mo before study tx, have an ECOG score 0-1, and have adequa...

A phase 2 randomized, double-blind, placebo-controlled trial of radium-223 dichloride with exemestane and everolimus in patients with HER2–negative hormone receptor–positive breast cancer and bone metastases.

TPS621Background: Treatment options for bone-dominant metastatic breast cancer (MBC) are limited.Radium-223 (Ra-223), a first-in-class α emitter with a targeted antitumor effect on bone metastases (mets), was well tolerated and reduced bone biomarker levels in a phase 2 study in patients with bone-dominant MBC (Coleman et al. Breast Cancer Res Treat 2014). In patients with HER2- estrogen receptor+ (ER+) bone-dominant MBC, everolimus + exemestane (EVE+EXE) improved progression-free survival (PFS) vs EXE alone. Ra-223 plus EVE+EXE may improve outcomes in patients with HER2- ER+ bone-dominant MBC; this trial will evaluate efficacy and safety of Ra-223 vs placebo in these patients (NCT02258451). Methods: Eligible patients are pre- or postmenopausal with HER2- ER+ MBC and ≥ 2 bone or soft tissue mets. Patients must have measurable disease per RECIST v1.1, ≥ 1 prior line of hormone therapy for MBC, and 1-2 prior skeletal-related events; be on bisphosphonates or denosumab; and have an ECOG score of 0-1. Patients...

Early experience with Puerto Rico: Effective use management of bone agents.

130 Background: Oncology Analytics is a cancer care decision support group recently entering the Puerto Rican cancer care marketplace. Bone agents are used in metastatic cancer management to delay the progression of lytic bone metastases. These agents are also used for the treatment of demonstrated osteoporosis with bone densitometry (DEXA scan). Oncology Analytics has found these agents are sometimes used in the absence of lytic metastases or osteoporosis. When this is discussed with treating physicians, practice patterns promptly improve. Beginning our work: The following work focuses entirely upon use among patients with bone mets. There is modest use of bone agents for bone mets among PR oncologists. A statistically significant decreasing and sustained trend in the inappropriate utilization of bone agents and especially the use of denosumab in the PR market is closely associated with recent initiation of OA decision support. Methods: We analyzed data from oncology drug preauthorization requests for bone modifying agents for the management of metastatic bone disease submitted by providers to payers serving in Puerto Rico from Jan 1, 2015 through September 30, 2015. Results: Within the 9 months, non-compliant zoledronic acid use diminished by one-third; pamidronate by 40%; and denosumab use was decreased by 75%. Quarterly dynamics demonstrates a statistically significant downward trend in the unnecessary use of these agents among PR oncologists (p,0.05). Conclusions: Oncology Analytics presence in a new market enhances cancer care quality and cancer care value quickly, while at the same time conserving substantial resources.

Abstract OT2-01-11: A phase 2 randomized, double-blind, placebo-controlled trial of radium-223 dichloride with exemestane and everolimus in human epidermal growth factor receptor 2–negative, hormone receptor–positive breast cancer patients with bone metastases

Abstract Background: Radium-223 dichloride (Ra-223), a first-in-class α-emitter with a potent, targeted antitumor effect on bone metastases (mets), was well tolerated and reduced baseline bone biomarker levels in a phase 2 study in metastatic breast cancer (MBC) patients (pts) with bone-dominant disease (Coleman et al. Breast Cancer Res Treat 2014). Adding everolimus (EVE) to exemestane (EXE) significantly improved progression-free survival (PFS) versus EXE alone in human epidermal growth factor receptor 2–negative (HER2-), hormone receptor–positive (HR+) MBC pts with advanced disease. This trial will evaluate efficacy and safety of Ra-223 with EXE and EVE in pts with HER2-, HR+ breast cancer and bone mets (NCT02258451). Trial design: Pts scheduled to receive EXE (25 mg PO once daily) and EVE (10 mg PO once daily) will be randomized 1:1 to Ra-223 (50 kBq/kg IV) or placebo × 6 cycles q4wk. EXE and EVE treatment (tx) will continue until disease progression, unacceptable toxicity, or the pt can no longer travel to the clinic to receive study medication. Stratification will be by geographic region, previous lines of hormone therapy, and presence of visceral disease. Safety and efficacy will be assessed at each 4-week clinic visit during tx. Long-term safety will be assessed until study termination (ie, pt death, pt loss to follow-up, or pt reaching required number of events). Main eligibility criteria: Eligible pts are pre- or postmenopausal with estrogen receptor–positive and HER2- bone lesion–related asymptomatic or mildly symptomatic MBC not amenable to cure by surgery or radiotherapy, and with ≥2 bone mets visible on bone scan. Pts must have measurable disease per RECIST v1.1, ≥1 prior line of hormonal therapy in the metastatic setting, and 1-2 skeletal related events before study entry; be on bisphosphonates or denosumab for ≥1 mo before study entry; and have ECOG performance status of 0-1, adequate hematologic, renal, and liver function, and life expectancy ≥6 mo. Pts may not have prior or current need for chemotherapy in the metastatic setting, unresolved spinal cord compression, and prior or current EVE tx. Specific aims: The primary endpoint is symptomatic skeletal event (SSE)–free survival. Secondary endpoints are overall survival, time to opiate use for cancer pain, time to pain progression, time to cytotoxic chemotherapy, radiologic PFS (rPFS), and acute and long-term safety. Exploratory endpoints include time to first on-study SSE, time to bone alkaline phosphatase (bALP) progression, bALP response at wk 12 and end of tx, bone-specific rPFS, resource utilization, biomarker assessments, and time to visceral mets onset. Statistical methods: Assuming a one-sided α of 0.1, power of 90%, ∼160 SSEs will be required at the time of analysis. A stratified log-rank test will be used to analyze efficacy (intent-to-treat population). Safety analysis will be descriptive. Present and target accrual: This trial is now enrolling pts. Target accrual is 311. Citation Format: Rugo HS, Huang L, Petrenciuc O, Zaccarini P, Coleman RE. A phase 2 randomized, double-blind, placebo-controlled trial of radium-223 dichloride with exemestane and everolimus in human epidermal growth factor receptor 2–negative, hormone receptor–positive breast cancer patients with bone metastases. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-01-11.