Petrylak, Daniel P.

5565 Background: mCRPC patients (pts) tend to have a poor prognosis and limited treatment (tx) options, especially those with concomitant bone metastases (mets). We explored the ability of combination tx with atezo (anti–PD-L1) and r-223 (α-particle emitter) to stimulate anti-tumor immunity in mCRPC pts. Methods: This Phase Ib study evaluated the safety and tolerability of atezo + r-223 in pts with mCRPC and multiple bone mets, visceral mets and/or lymphadenopathy who progressed after androgen pathway inhibitor tx. The initial cohort phase evaluated the safety and tolerability of a concurrent dosing schedule (CDS), in which atezo and r-223 were administered on the same day. Following assessment of CDS, pts were randomized 1:1:1 to CDS or 1 of 2 staggered dosing schedules (atezo or r-223 introduced a full cycle before the other). This was followed by an expansion of enrollment (randomized 1:1:1). Pts got atezo 840 mg IV q2w and r-223 at 55 kBq/kg IV 6 times at 4-wk intervals until unacceptable toxicity or loss of clinical benefit. Exploratory measures of efficacy included investigator-assessed ORR (RECIST 1.1), PSA response rate, time to PSA progression, radiographic PFS (rPFS; PCWG2 criteria) and OS. Biopsy samples were collected at baseline and prior to cycle 2 to evaluate changes in the tumor microenvironment during tx. Results: As of Oct 4, 2019, 45 pts were enrolled and 44 had evaluable data. Baseline characteristics were generally similar across groups. All 44 evaluable pts had ≥ 1 all-cause AE; 23 (52.3%) had Gr 3-4 AE. Eight pts (18.2%) had Gr 5 AE as per protocol reporting of deaths; 4 (9.1%) were from disease progression. Median follow-up was 13.9 mo (range, 1.7–34.2). Confirmed ORR was 6.8% (95% CI: 1.43, 18.66). Confirmed PSA response rate was 4.5% and median time to PSA progression was 3.0 mo (95% CI: 2.8, 3.3). Median rPFS was 3.0 mo (95% CI: 2.8, 4.6) and median OS was 16.3 mo (95% CI: 10.9, 22.3). Changes in PD-L1 and CD8 IHC were consistent with the known mechanism of action of atezo, as were changes in alkaline phosphatase with radium. Conclusions: No dose-limiting toxicities, safety signals, or changes in serum biomarkers were observed beyond the known safety profiles of atezo and r-223. This Phase 1b study did not seem to show clinical benefit from combination tx. Ongoing subgroup and biomarker analyses may provide additional insights. Studies of PD-1/PD-L1 targeted therapies in combination with tumor-directed radiation in molecularly selected mCRPC pts are planned or underway. Clinical trial information: NCT02814669 .

AbstractBackgroundProstate‐specific membrane antigen (PSMA) is a well‐established therapeutic and diagnostic target overexpressed in both primary and metastatic prostate cancers. PSMA antibody‐drug conjugate (PSMA ADC) is a fully human immunoglobulin G1 anti‐PSMA monoclonal antibody conjugated to monomethylauristatin E, which binds to PSMA‐positive cells and induces cytotoxicity. In a phase 1 study, PSMA ADC was well tolerated and demonstrated activity as measured by reductions in serum prostate‐specific antigen (PSA) and circulating tumor cells (CTCs). To further assess PSMA ADC, we conducted a phase 2 trial in metastatic castration‐resistant prostate cancer (mCRPC) subjects who progressed following abiraterone/enzalutamide (abi/enz) therapy.MethodsA total of 119 (84 chemotherapy‐experienced and 35 chemotherapy‐naïve) subjects were administered PSMA ADC 2.5 or 2.3 mg/kg IV q3w for up to eight cycles. Antitumor activity (best percentage declines in PSA and CTCs from baseline and tumor responses through radiological imaging), exploratory biomarkers, and safety (monitoring of adverse events [AEs], clinical laboratory tests, and Eastern Cooperative Oncology Group performance status) were assessed.ResultsPSA declines ≥50% occurred in 14% of all treated (n = 113) and 21% of chemotherapy‐naïve subjects (n = 34). CTC declines ≥50% were seen in 78% of all treated (n = 77; number of subjects with ≥5 CTCs at baseline and a posttreatment result) and 89% of chemotherapy‐naïve subjects (n = 19); 47% of all treated and 53% of chemotherapy‐naïve subjects had a transition from ≥5 to less than 5 CTCs/7.5 mL blood at some point during the study. PSA and CTC reductions were associated with high PSMA expression (CTCs or tumor tissue) and low neuroendocrine serum markers. In the chemotherapy‐experienced group, the best overall radiologic response to PSMA ADC treatment was stable disease in 51 (60.7%) subjects; 5.7% of subjects in the chemotherapy‐naïve group had partial responses. The most common treatment‐related AEs ≥Common Terminology Criteria for AE (CTCAE) grade 3 were neutropenia, fatigue, electrolyte imbalance, anemia, and neuropathy. The most common serious AEs were dehydration, hyponatremia, febrile neutropenia, and constipation. Two subjects who received 2.5 mg/kg died of sepsis.ConclusionsPSMA ADC demonstrated some activity with respect to PSA declines, CTC conversions/reductions, and radiologic assessments in abi/enz treated mCRPC subjects. Clinically significant treatment‐related AEs included neutropenia and neuropathy.

5031 Background: The phase 2 TRITON2 study (NCT02952534) is evaluating the PARP inhibitor rucaparib in patients with mCRPC who have a deleterious germline or somatic alteration in BRCA ( BRCA1 or BRCA2) or 1 of 13 other DNA damage repair genes. Here we present analyses of tumor genomics and baseline clinical characteristics in mCRPC patients with a deleterious alteration in BRCA. Methods: Plasma (baseline) and tissue (archival or baseline) samples from patients with a deleterious alteration in BRCA were analyzed using Foundation Medicine next-generation sequencing assays. The alterations and zygosity of the alterations that were detected, as well as the somatic/germline status from Color Genomics testing, were summarized. Associations between genomic alterations, DNA yield, allele frequency, and baseline clinical characteristics were investigated. Results: Results are shown in the Table for a cohort of 40 BRCA2 and 5 BRCA1 patients enrolled in TRITON2 (Abida W et al. Presented at ESMO 2018. Abst 793PD). A biallelic alteration was observed in 21 of the 22 BRCA2 patients (95%) for whom alteration zygosity could be determined. Among the 5 BRCA1 patients, 1 alteration was monoallelic and 4 were of unknown zygosity. Co-occurring alterations in cancer-related or DNA damage repair genes were observed in many patients with BRCA alterations. At baseline, cell-free DNA (cfDNA) yield correlated positively with the sum of target lesions (STL; P= 0.04), but not with prostate-specific antigen (PSA) levels ( P= 0.86). No correlation was observed between allele frequency of the BRCA alteration baseline STL ( P= 0.68) or PSA levels ( P= 0.97). Conclusions: Patients with a BRCA mutation enrolled in TRITON2 demonstrate a profile of genomic alterations consistent with that of prior studies of patients with mCRPC. Plasma cfDNA profiling showed a correlation between baseline cfDNA yield and measurable tumor burden, but not baseline PSA. Clinical trial information: NCT02952534. [Table: see text]

TPS389 Background: Recent data have shown that up to 25% of patients with advanced prostate cancer, including mCRPC, have a deleterious germline or somatic mutation in BRCA1, BRCA2, ATM, or another homologous recombination DNA repair gene. Such mutations can be used as a molecular marker to select patients for targeted treatment with poly(ADP-ribose) polymerase inhibitors (PARPis), which are lethal to cells with HRD. Treatment with PARPis has shown preliminary evidence of antitumor activity in patients with mCRPC and a mutation in a homologous recombination DNA repair gene (Mateo et al. N Engl J Med. 2015;373:1697-708). These data provide a compelling rationale for evaluating rucaparib, a potent inhibitor of PARP1, PARP2, and PARP3, in patients with mCRPC associated with HRD. Methods: TRITON3 (NCT02975934) is a randomized, phase 3 study evaluating rucaparib 600 mg BID vs physician’s choice of abiraterone, enzalutamide, or docetaxel in patients with mCRPC and a deleterious germline or somatic BRCA1, BRCA2, or ATM mutation (identified by prior local testing or central testing during screening). Patients must have progressed on androgen receptor signaling–directed therapy in the mCRPC setting; prior PARPi treatment or chemotherapy for mCRPC are exclusion criteria. Patients will be randomly assigned in a 2:1 ratio to either rucaparib or physician’s choice, with the possibility for cross over from the comparator treatment to rucaparib upon radiographic progression confirmed by independent radiology review. The primary endpoint is radiographic progression-free survival (modified RECIST v1.1/PCWG3 criteria) assessed by independent radiology review. Secondary endpoints include objective response rate, duration of response, patient-reported outcomes, overall survival, and safety. Pretreatment blood samples collected from all patients will enable development of a noninvasive plasma-based companion diagnostic to select patients who may benefit from rucaparib treatment. Patients (≈400) will be enrolled at > 100 sites worldwide. Clinical trial information: NCT02975934.

TPS388 Background: Up to 25% of patients with advanced prostate cancer, including mCRPC, have a deleterious germline or somatic mutation in BRCA1, BRCA2, ATM or another homologous recombination (HR) DNA repair gene that can serve as a molecular marker to select those who may respond to poly(ADP-ribose) polymerase inhibitors (PARPis). PARPis are lethal to cells with HRD, and PARPi treatment has shown preliminary evidence of an antitumor effect in patients with mCRPC who harbor a mutation in an HR DNA repair gene (Mateo et al. N Engl J Med. 2015;373:1697-708). These data provide a compelling rationale for evaluating rucaparib, a potent PARP1, PARP2 and PARP3 inhibitor, in patients with mCRPC associated with HRD. Methods: TRITON2 (NCT02952534) is a phase 2 study evaluating rucaparib 600 mg BID in patients with mCRPC. Patients with a deleterious germline or somatic BRCA1, BRCA2 or ATM mutation (per prior local test or central test during screening) will be enrolled into 1 of 2 cohorts based on the presence or absence of measurable visceral and/or nodal disease. An exploratory cohort will enroll patients with an alteration in any of 12 other prespecified HR genes (eg, RAD51C, RAD51D and PALB2), with or without measurable visceral and/or nodal disease. Patients must have progressed on androgen receptor signaling–directed therapy and 1 prior taxane-based chemotherapy for mCRPC. Patients who received prior treatment with a PARPi, mitoxantrone, cyclophosphamide or platinum-based chemotherapy are excluded. The primary endpoint is objective response rate measured using modified RECIST v1.1/PCWG3 for patients with soft-tissue disease and prostate-specific antigen response for patients with nonmeasurable disease. Secondary endpoints include duration of response, radiographic progression-free survival, overall survival, clinical benefit rate and safety. Pretreatment blood samples collected from all patients will enable development of a plasma-based companion diagnostic to select patients who may benefit from rucaparib treatment. Patients (≈160) will be enrolled at > 100 sites worldwide. Clinical trial information: NCT02952534.

295 Background: Patients (pts) with metastatic urothelial carcinoma (UC) progressing after first-line chemotherapy have limited treatment options. Ramucirumab (Ram), a human VEGFR2-targeted mAb, has demonstrated clinical activity in several solid tumors. Preclinical testing supports a role for Ram-taxane combinations in UC. Study JCDC is an open-label, multicenter, randomized phase 2 study of docetaxel (Doc) alone or combined with Ram or icrucumab (Icr) in locally advanced or metastatic platinum-resistant UC. We report on a planned interim analysis for Doc + Ram vs Doc; Icr results will be reported later. Methods: Eligible pts with advanced UC and ECOG PS 0-1 who relapsed ≤ 1 year from a platinum-regimen were randomized to receive Doc 75 mg/m2IV alone or with Ram 10mg/kg IV on Day 1 of repeating 21-day cycles. A sample size of 46 pts per arm enabled 71% power to demonstrate statistical significance of 4.5 mo (Doc + Ram) vs 3 mo (Doc) at a 1-sided α= 0.1. Treatment continued until disease progression or unacceptable toxicity. The primary endpoint is investigator-assessed PFS with RECIST v1.1, analyzed by K-M methods. A planned interim analysis was performed after 75% of the PFS events. Results: 44 pts received Doc and 46 received Doc + Ram. Study arms were well matched with a mean age of 67 yr (29-84), and a 4:1 male to female ratio. 58.7% (Doc + Ram) vs 61.4% (Doc) had ECOG PS 1. 58.7% (Doc + Ram) vs 52.3% (Doc) had visceral metastases. Doc + Ram reduced the risk of disease progression, stratified HR = 0.388; 95% CI: 0.222, 0.677; log-rank p = 0.0005, improving median PFS (5.1 vs 2.4 mo). The ORR for Doc + Ram was 19.6 vs 4.5% for Doc (p= 0.0502), and the disease control rate was 67.4 vs 43.2%. OS maturity is pending. The most common adverse events in the Doc + Ram arm (all grades) were fatigue (80.4% Doc + Ram v 75.0% Doc), decreased appetite (54.3 v 43.2%), nausea (54.3 v 25.0%), and neuropathy (50.0 v 38.6%). Grade (G) ≥3 febrile neutropenia (19.6 v 11.4%), pneumonia (13 v 9.1%), hypertension (4.3 v 0%) were higher with Doc + Ram. One G3 hematuria was observed in each arm. Conclusions: Results support a statistically significant improvement in PFS for Doc + Ram in second-line UC. Final results are expected in 2015. Clinical trial information: NCT01282463.

265 Background: UC response to CT is not durable. Angiogenesis may play a role in the progression of UC. We evaluated whether maintenance sunitinib delays progression after response to CT. Methods: Pts with ECOG PS 0-2, adequate organ function, stable disease, partial or complete response (SD, PR, CR) after 4-6 cycles of CT for advanced UC were randomized to oral sunitinib 50 mg/day, 28 days on, 14 days off (6-week cycle) or placebo. Disease was assessed every 12 wks. At progression, placebo pts were offered open label sunitinib. Primary endpoint: progression rate at 6 months (ms); secondary endpoints: safety, objective response rate, survival, VEGF/sVEGFR2 serum level changes. Using a randomized selection design 42 pts/arm has 90% probability of selecting sunitinib if true reduction in 6-ms progression rate is 15% (from 50% to 35%). Results: Study was closed early due to slow accrual. 54 pts with median age 69 years, median ECOG PS 1, 70% with bladder primary, 26 with SD, 23 with PR, 5 with CR to CT were randomized to sunitinib (26) or placebo (28). The median number of cycles was 2/arm (sunitinib 0-15, placebo 0-13). The 6-ms progression rate was 81% (95%CI 61-93%), median time-to-progression (TTP) 5 ms (0.3-22.2, 95%CI 2.4-6.3) for sunitinib and 75% (95%CI 55-89%), 2.7 ms (0.8-19.6, 95%CI 2.5-7.4) for placebo. Response rate in pts with SD at enrollment was 9% for sunitinib and 7% for placebo. Most common G3/4 AEs on sunitinib were diarrhea (15.4%/0%), fatigue (15.4%/3.8%), thrombocytopenia (15.4%/7.7%), hypertension (11.5%/0%). 16 placebo pts received sunitinib with best response 1 PR (6.25%), 6 SD (37.5%), 5 PD (31.25%); 4 not response evaluable. Median TTP was 3.4 ms (0.1-22, 95%CI 1.6-5.5). 11 pts had G3/4 AEs, 5 pts discontinued sunitinib due to AEs (4 related, 1 unrelated). Placebo pts had no change in VEGF/sVEGFR2 over time. Sunitinib pts had no change in VEGF but sVEGFR2 significantly decreased after 1 cycle (p<0.0001) and at progression (p=0.0002). VEGF/sVEGFR2 did not correlate with TTP. Conclusions: Maintenance sunitinib was feasible but did not improve 6-ms progression rate; open label sunitinib had limited activity. sVEGFR-2 decreased on sunitinib.