Bryce, Alan H.

8116 Background: POEMS syndrome, or osteosclerotic myeloma, is an uncommon plasma cell disorder associated with Peripheral neuropathy, Organomegaly, Endocrinopathy, M protein, and Skin changes, as well as bone lesions, Castlemans disease, and edema. The pathogenesis of POEMS is poorly understood, and its clinical course is distinct from Multiple Myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS). While various cytogenetic abnormalities have been well described in MM and MGUS, we provide the first report of testing for these abnormalities in POEMS syndrome. Methods: Using a prospectively held dysproteinemia database, we reviewed all cases of POEMS seen at our institution, identifying 36 with metaphase cytogenetic testing results, and 9 with fluorescence in situ hybridization (FISH) testing results. Combined cytoplasmic immunoglobulin/FISH testing (cIg- FISH) was performed with fluorescent-tagged antibodies to kappa/lambda immunoglobulin and FISH probes corresponding to the following anomalies: trisomies 3, 7, 9, 11, 15 and 17; del13/del13q; 14q32 split/del14; and t(11;14). Results: Five patients had insufficient plasma cells for cIg-FISH, and 9 were adequate for testing. Monosomy 13 was seen in 5 of the 9 cIg-FISH samples of which 2 of these cases also had apparent monosomy 14. cIg-FISH in one patient revealed trisomy 3 and 7. No abnormalities were seen at 11q13 (CCND1), 17p13 (p53) or translocations involving 14q32 (IGH). Thrity-eight total karyotypes analyses were attempted, though two showed an insufficient number of suitable metaphases. Of the 36 karyotype analyses, 31 were normal, 2 displayed characteristic plasma cell anomalies (hyperdiploid with structural anomalies), 2 treated patients displayed del20q anomalies and 1 patient had a constitutional 13;14 translocation. Conclusion: We are the first to report del13 as a possibly common abnormality in POEMS syndrome, detected by cIg-FISH in 5 of 9 (55%) samples with sufficient plasma cells, similar to the rate observed in MM and MGUS. The lack of abnormalities at 14q32 (IgH locus) is in contrast to MM and MGUS. Abnormal karyotypes, consistent with dividing plasma cells, are rare in POEMS, observed in only 2 of 36 (5.5%) cases. These observations could possibly lend insight into all three disorders. No significant financial relationships to disclose.

Abstract Purpose: Genomic alterations in DNA damage repair (DDR) genes other than BRCA may confer synthetic lethality with PARP inhibition in metastatic castration-resistant prostate cancer (mCRPC). To test this hypothesis, the phase II TRITON2 study of rucaparib included patients with mCRPC and deleterious non-BRCA DDR gene alterations. Patients and Methods: TRITON2 enrolled patients who had progressed on one or two lines of next-generation androgen receptor–directed therapy and one taxane-based chemotherapy for mCRPC. Key endpoints were investigator-assessed radiographic response per modified RECIST/PCWG3 and PSA response (≥50% decrease from baseline). Results: TRITON2 enrolled 78 patients with a non-BRCA DDR gene alteration [ATM (n = 49), CDK12 (n = 15), CHEK2 (n = 12), and other DDR genes (n = 14)]. Among patients evaluable for each endpoint, radiographic and PSA responses were observed in a limited number of patients with an alteration in ATM [2/19 (10.5%) and 2/49 (4.1%), respectively], CDK12 [0/10 (0%) and 1/15 (6.7%), respectively], or CHEK2 [1/9 (11.1%) and 2/12 (16.7%), respectively], including no radiographic or PSA responses in 11 patients with confirmed biallelic ATM loss or 11 patients with ATM germline mutations. Responses were observed in patients with alterations in the DDR genes PALB2, FANCA, BRIP1, and RAD51B. Conclusions: In this prospective, genomics-driven study of rucaparib in mCRPC, we found limited radiographic/PSA responses to PARP inhibition in men with alterations in ATM, CDK12, or CHEK2. However, patients with alterations in other DDR-associated genes (e.g., PALB2) may benefit from PARP inhibition. See related commentary by Sokolova et al., p. 2439

83 Background: PT-112, the first pyrophosphate conjugate in Phase I/II clinical development, induces robust immunogenic cell death and is osteotropic, prompting study in mCRPC during Phase I. We report safety and efficacy findings in the mCRPC sub-population given PT-112 monotherapy (NCT02266745) or in combination with avelumab (“PAVE”) (NCT03409458, ongoing). Methods: Patients (pts) received PT-112 days 1, 8, 15 of a 28d cycle; pts on the PAVE combination also received 800 mg avelumab days 1 and 15; all enrolled during dose escalation or at PT-112 doses previously deemed safe. Pts on therapy (Tx) for ≥2 cycles or who stopped Tx due to progressive disease or treatment-related adverse events (TRAEs) were evaluated for exploratory efficacy. Results: 10 pts on PT-112 (200-420 mg/m2) and 18 pts on PAVE (150-200 mg/m2 PT-112) were evaluable for safety. The most common PT-112 TRAEs were thrombocytopenia (70%, grade (Gr) ≤3) and fatigue (40%, Gr ≤2) with mono-Tx; nausea (50%, Gr ≤2) and fatigue (39%, Gr ≤2) with PAVE. Mono-Tx pts had 6.5 median prior lines of Tx; 2/7 pts with measurable disease (MD) had reductions in target lesions; prostate specific antigen (PSA) declined in 3/10 pts, 1 with ≥50% reduction; and serum alkaline phosphatase (ALP) reductions were seen in 9/10 pts. PAVE pts had 5.5 median prior lines of Tx; radiographic reductions were seen in 2/9 pts with MD; PSA declined in 6/14 pts, 3 with ≥50% decrease, with 1 responder progression free 11.3 months (microsatellite stable). An additional response is ongoing at 4 mos, with 93% PSA decrease and 48% reduction in target lesions (PIK3CBmut & PTEN loss). 13/14 pts with bone metastases had ALP reductions. Pain improvement, opioid cessation and improved performance status were noted in both cohorts. Conclusions: PT-112 was well-tolerated with evidence of efficacy in mCRPC as mono-Tx and in combination with avelumab in heavily pre-treated pts. Bone pain improvement and nearly universal observation of ALP reduction suggest marked therapeutic activity of PT-112 in bone metastases. Serologic / RECIST responses and prolonged disease control in multiple pts substantiate further development of PT-112 in mCRPC. Clinical trial information: NCT02266745, NCT03409458.

696 Background: A number of treatments for metastatic renal cell carcinoma (RCC) have been FDA approved since December, 2005. Trials evaluating these agents excluded non-clear cell histologies and therefore the efficacy of these treatments remains unclear in patients (pts) with metastatic non-clear cell RCC (mncRCC). Methods: This is a single arm Phase II study designed to determine the efficacy of pazopanib in mncRCC. Treatment was pazopanib 800 mg by mouth daily until progression or intolerability of treatment. Dose reductions were allowed for toxicity with dose level -1 being 600 mg daily and dose level -2, 400 mg daily. Cycles were every 28 days. Main eligibility criteria included: (1) age ³ 18 years old; (2) histologic confirmation of ncRCC; (3) ECOG Performance Status (PS) 0, 1, or 2; (4) up to one prior treatment for mncRCC (5) measurable or non-measurable metastatic disease per RECIST criteria. The primary endpoint was overall survival rate at 12 months. Secondary endpoints were best tumor response rates after two cycles, PFS, OS and toxicity. Results: 38 pts were enrolled between May 16, 2013 and February 1, 2018. 35 pts were evaluable for primary endpoint. Median age 63 years old and 22/35 (62.9%) were male. Most common histology was papillary RCC, 14/35 (40%), and most common number of metastatic sites was 1. 29/35 (82.9%) had prior nephrectomy and 30/35 (85.7%) had no prior systemic therapy. Median number of cycles was 5. 12-month OS was 65.7% (90% CI, 50.5-78.9%). Best response in first 2 cycles: PR 11%, SD 60%, PD 9%, not evaluated 20%. Median PFS was 7.5 months (90% CI, 5.0-11.0); median OS 18.9 months (90% CI, 13.0-NE). Grade 3 / 4 AEs seen in 25 pts with hypertension, transaminitis and abdominal pain being most common (seen in >10%). Conclusions: There are limited data about the efficacy of available therapies for mncRCC. This study shows that pazopanib has similar efficacy compared to historical data in clinical trials using other TKIs in mncRCC. The safety profile of pazopanib in pts with mncRCC was found to be similar to that found in prior clinical trials studying pazopanib. Our findings warrant further investigation into the utility of pazopanib in metastatic ncRCC. Clinical trial information: NCT01767636.

320 Background: While there is no standard therapy for BCR PC following local therapy, intermittent ADT is widely used. We evaluated utility of APA alone, ADT (luteinizing hormone–releasing hormone agonist [LHRHa]) alone, or APA + LHRHa in ADT-naïve BCR PC pts. Methods: Pts with BCR PC after primary definitive local therapy and prostate-specific antigen (PSA) doubling time (PSADT) ≤ 12 mo were randomized 1:1:1 to open-label 240 mg APA daily, LHRHa alone, or APA + LHRHa for 12 mo, followed by a 12-mo observation period off therapy. Pts were stratified by PSADT (< 6 vs 6-12 mo) and age (≤ 70 vs > 70 y). Primary end point: mean change from baseline (BL) in health-related quality of life (HRQoL) per Functional Assessment of Cancer Therapy-Prostate total score at 12 mo. Secondary end points included PSA nadir < 0.2 ng/mL by 7 mo, time to PSA progression (TTPpsa), and time to testosterone (T) recovery. Results: 90 pts (APA, n = 29; LHRHa, n = 30; APA + LHRHa, n = 31) were treated for median of 12 mo with similar distribution of BL characteristics across groups: 67% age ≤ 70 y; 67% PSADT < 6 mo. There was no significant difference in HRQoL in APA vs LHRHa at 12 mo, or between LHRHa vs APA + LHRHa groups. At median follow-up of 30-33 mo, TTPpsa in APA, LHRHa, and APA + LHRHa groups was 26 mo, 31 mo, and 36 mo, respectively. Compared to LHRHa alone, APA + LHRHa resulted in a trend toward improved TTPpsa (HR [95% CI] 0.56 [0.23-1.36], p = 0.196), and APA alone resulted in a trend for shorter TTPpsa (HR 1.09 [0.49-2.43], p = 0.824). PSA nadir < 0.2 ng/mL was reached in 89%, 89%, and 97% in APA, LHRHa, and APA + LHRHa pts. Median time to T recovery was similar in LHRHa and APA + LHRHa groups (23 mo vs 24 mo). Grade 3-4 adverse events (AEs) occurred in 17% of APA, 14% of LHRHa, and 29% of APA + LHRHa pts. The only grade 3-4 AE reported in > 1 pt per group was hypertension (APA, 3%; LHRHa, 0; APA + LHRHa, 13%). Conclusions: Addition of APA to LHRHa resulted in a trend for longer TTPpsa and a higher proportion of pts achieving optimal PSA nadir without significant difference in HRQoL or time to T recovery. Observed AEs were consistent with known safety profiles. Results support further evaluation of APA + LHRHa for a specified duration in BCR PC. Clinical trial information: NCT01790126.

30 Background: BM in patients (pts) with CRPC are associated with shorter overall survival (OS) and higher costs. BRI zoledronic acid and denosumab are frequently used to prevent skeletal-related events (SRE) in pts with CRPC and BM. AA is the most common 1st line therapy for men with metastatic CRPC. We aimed to assess the impact of BRI on OS and time to first SRE (ttSRE) of pts receiving 1st line treatment AA for CRPC with BM. Methods: A retrospective cohort of pts starting AA as 1st line therapy for CRPC with BM between 2013-2016 was identified through 8 hospitals’ IRB approved registries. Pts were classified by use of concomitant BRI and subgrouped by volume of disease (per E3805 definition) at AA start. Kaplan-Meier method and Cox models were used to assess OS and ttSRE with hazard ratio (HR) estimates (95% CI). Results: Of the 745 pts included (543 deaths), 529 (71.0%) had AA alone and 216 (29.0%) AA+BRI. Median follow-up was 23.5 months. Pts receiving concomitant BRI showed a significantly longer OS and a 35% reduced risk of death compared to AA alone (HR=0.65; 95% CI, 0.54-0.79; P<.0001). The OS benefit with BRI was greater for the subgroup with high volume disease (HV) (HR=0.51; 95% CI, 0.38-0.68; P<.0001). The cohort with AA+BRI had a significantly shorter ttSRE (HR=1.27; 95% CI; 1.0-1.60; P=.0439) and, notably, the risk of first SRE was more than doubled for the subgroup with LV (HR=2.29; 95% CI, 1.57-3.35; P<.0001). On MVA, BRI vs. no BRI, prior local therapy (PLT) vs. no PLT, LV vs. HV, baseline VAS pain ≤3 vs. >5, PS 0 vs. ≥1, and PSA are independently associated with longer OS. Conclusions: The addition of BRI to 1st line AA for CRPC men with BM was associated with improved OS, particularly in HV, and worsened ttSRE, more evident in LV. These data suggest a potentially different impact of concomitant BRI on HV vs. LV, which could affect clinical decision making.[Table: see text]

178 Background: The phase 2 TRITON2 study (NCT02952534) is evaluating the PARP inhibitor rucaparib in pts with mCRPC and a deleterious germline or somatic alteration in BRCA ( BRCA pts) or 1 of 13 other DNA damage repair (DDR) genes. Methods: Eligible pts had progressed on 1–2 lines of androgen receptor-directed therapy and 1 taxane-based chemotherapy. Deleterious DDR gene alterations were identified from central testing of plasma and/or tissue samples by Foundation Medicine or from local testing. Results: As of Jul 2, 2019 (visit cutoff), 98 BRCA pts had received rucaparib; median (range) duration of follow-up was 13.0 (4.1–25.8) mo. Confirmed objective response rate (ORR) in BRCA pts (with investigator-assessed measurable disease) and PSA response rates (in pts with and without measurable disease) are shown in the Table. A biallelic alteration was observed in 81.4% (35/43) of BRCA pts for whom zygosity could be determined, and pts with homozygous BRCA loss (20.4%; 20/98) demonstrated high ORR (66.7% [95% CI, 38.4-88.2]; 10/15) and PSA response rates (75.0% [95% CI, 50.9-91.3]; 15/20). The safety profile in BRCA pts was consistent with the overall TRITON2 pt population. Conclusions: Results from TRITON2 showed antitumor activity with rucaparib in pts with mCRPC and a deleterious BRCA alteration. Responses were observed in patients with germline or somatic alterations in BRCA1 or BRCA2. The activity of rucaparib in these and additional genomic subgroups (e.g., based on zygosity, plasma genomic testing, or co-occurring alterations) will be reported. Clinical trial information: NCT02952534. [Table: see text]

144 Background: Despite having well-recognized limitations, urologists often rely on serial PSA testing as a marker for treatment response or disease progression. To determine if PSA was indeed a reliable marker for treatment response or disease progression, we compared PSA levels against C-11 choline PET/CT in the evaluation of patients with advanced prostate cancer treated with second generation hormonal therapy (2nd-HT). Methods: We retrospectively identified 239 patients who were undergoing treatment with 2nd-HT (enzalutamide or abiraterone) for advanced prostate cancer. While on treatment, patients underwent serial PSA testing and C-11 choline PET/ CTs every 3 – 6 months. Paradoxical response was defined as increasing blood pool-corrected SUVmax of known choline-avid lesions and/or identification of new choline-avid lesions, despite stable or down-trending PSA. Results: Median (IQR) age was 70.4(64.3 – 75.7) years and median (IQR) primary Gleason Score was 8 (7 – 9). In our study, 19% of patients (n = 46/239) who were receiving 2nd-HT exhibited paradoxical response. Median (IQR) PSA and corrected SUVmax at baseline evaluation were 1.3 ng/mL (0.3 – 12.8 ng/mL) and 3.5 (1.8 – 5.8), respectively. Median (IQR) PSA and corrected SUVmax at the time of paradoxical response were 0.4 ng/mL (0.1 – 5.4 ng/mL) and 4.5 (2.8 – 6.8), respectively. The median duration of 2nd-HT treatment prior to detection of paradoxical response was 4.8 months (2.9 – 10.1 months). No significant difference was noted between patients receiving enzalutamide versus abiraterone (p = 0.35). Independent predictors of paradoxical response were prior primary systemic treatment (i.e. hormonal/chemo-hormonal therapy versus local therapy) and patient’s age at time of 2nd-HT initiation on univariate and multivariate analysis. Conclusions: Our retrospective review demonstrated prostate cancer disease progression discordant with PSA down-trending in 19% of patients receiving 2nd-HT. We conclude that in this subset of patients with advanced prostate cancer, PSA may not be a reliable marker of treatment response of disease progression, and routine radiographic evaluation in these patients is warranted.

Cutaneous melanoma metastases can contribute to visual disturbances through a variety of factors, including metastasis to the vitreal fluid. The optimum management of metastatic cutaneous melanoma to the vitreal fluid is unknown, but can include radiation therapy or systemic therapy including immunotherapy. A high degree of suspicion is necessary to consider this complication while working with patients with cutaneous melanoma.

AbstractBackgroundOptimal sequencing of systemic therapy in the management for metastatic castration resistant prostate cancer (mCRPC) remains poorly elucidated. The CHAARTED and STAMPEDE studies have proven that early chemotherapy in the hormone‐sensitive setting yields a greater net survival advantage than docetaxel for mCRPC. In a retrospective study, we attempt to investigate the two most common treatment sequences for mCRPC and investigate whether earlier chemotherapy for mCRPC is consequential to survival outcomes.MethodsWe identified 112 patients with mCRPC treated at the Mayo Clinic between 2011 and 2017. We identified two cohorts, 80 patients (group A) received full course docetaxel chemotherapy followed by second generation hormone therapy (2nd gen androgen deprivation therapy [ADT]; Abiraterone or Enzalutamide) and 32 patients (group B) treated with 2nd gen ADT followed by docetaxel. The primary endpoint evaluated was 3‐year cancer‐specific survival.ResultsMean prostate specific antigen at initiation of first treatment was 32.0 in group A and 21.7 in group B (P = .4). Bone metastases were more prevalent in group B (87% vs 58%, P = .01). All other clinicopathologic variables were statistically similar between group A and group B. Three‐year cancer‐specific survival was 87.4% vs 64.1% for group A and group B, respectively (P = .016). We report a univariate hazard ratio of 3.61 (95% CI, 1.74‐9.5, 0 P = .01). Three‐year overall survival was 82.4% and 60.8% for group A and group B, P = .01. These results held true when excluding patients with lymph node only metastasi.ConclusionOur data indicates that sequence of systemic therapy may influence outcomes for mCRPC and that docetaxel should be considered before 2nd generation ADT. Our results support the importance of earlier chemotherapy in the castration resistant state.