A Phase IB Trial of the PI3K Inhibitor Alpelisib and Weekly Cisplatin in Patients with Solid Tumor Malignancies.

The PI3K pathway may be a potential mechanism to overcome cisplatin resistance. We conducted a phase Ib trial of alpelisib and cisplatin for patients with solid tumor malignancies with planned dose expansion in HPV-associated tumors. The primary objective was to determine the MTD and recommended phase II dose. Two different weekly doses of cisplatin (30 and 35 mg/m2) were evaluated with escalating doses of alpelisib, administered daily during a 21-day treatment cycle. Twenty-three patients were enrolled: 91% received >3 prior regimens with median of 4 (range 1-10), and 78% progressed on prior platinum. The MTD was alpelisib 250 mg daily with weekly cisplatin 30 mg/m2. There were 3 DLTs: all grade 4 hyperglycemia. Frequent treatment-related adverse events of any grade included fatigue (52%), diarrhea (39%), nausea (38%), hyperglycemia (30%), anemia (22%), and nephropathy (17%). Hyperglycemia was linked to baseline hemoglobin A1C, but not body mass index. Twelve patients discontinued treatment for toxicity (n = 9 during cycle 1) and 11 discontinued for progression. Of 14 evaluable patients who received at least one treatment cycle, 4 (29%) patients demonstrated partial response, and 7 had stable disease for a disease control rate of 79%. The median PFS measured 4.3 months (95% CI, 1.6-4.5). No difference in PFS was observed between PIK3CA-mutated and wild-type tumors. While the combination of alpelisib and cisplatin demonstrated preliminary evidence of activity despite platinum resistance, toxicities hindered prolonged treatment. Prospective studies are planned using carboplatin and alpelisib to improve toxicity and tolerability. Significance: The PI3K inhibitor alpelisib has limited activity alone, but there is interest in combinations in platinum-resistant tumors. In this phase Ib study of alpelisib with cisplatin, the objective response rate measured 29% but adverse events limited dose intensity. These promising results provide rationale for studying combinations with better tolerated platinum agents.

Differential treatment outcomes in BRCA1/2-, CDK12-, and ATM-mutated metastatic castration-resistant prostate cancer.

BACKGROUND: DNA damage repair mutations (DDRm) are common in patients with metastatic castration-resistant prostate cancer (mCRPC). The optimal standard therapy for this population is not well described. METHODS: A multi-institutional, retrospective study of patients with mCRPC and DDRm was conducted. Patient data, including systemic therapies and responses, were collected. The decline in prostate-specific antigen ≥ 50% from baseline (PSA50) and overall survival (OS) from the treatment start were compared by mutation and treatment type. A multivariable Cox proportional hazards model for OS was created that controlled for DDRm, first-line treatment received for mCRPC, and clinical factors. RESULTS: The most common DDRm observed among 149 men with mCRPC were BRCA1/2 (44%), CDK12 (32%), and ATM (15%). The majority received first-line abiraterone (40%) or enzalutamide (30%). The PSA50 rate with first-line abiraterone was lower for CDK12 (52%) than BRCA1/2 (89%; P = .02). After first-line abiraterone or enzalutamide, the median OS was longest with second-line carboplatin-chemotherapy (38 months) in comparison with abiraterone or enzalutamide (33 months), docetaxel (17 months), or cabazitaxel (11 months; P = .02). PSA50 responses to carboplatin-based chemotherapy were higher for BRCA1/2 (79%) than ATM (14%; P = .02) or CDK12 (38%; P = .08). In a multivariable analysis, neither the specific DDRm type nor the first-line treatment was associated with improved OS. CONCLUSIONS: Responses to standard therapies were generally superior in patients with BRCA1/2 mutations and inferior in patients with ATM or CDK12 mutations. The DDRm type did not independently predict OS. After progression on first-line abiraterone or enzalutamide, carboplatin-based chemotherapy was associated with the longest OS. These findings may inform treatment discussions and clinical trial design and require prospective validation.

Differential Toxicity in Patients with and without DNA Repair Mutations: Phase I Study of Carboplatin and Talazoparib in Advanced Solid Tumors.

Purpose: The PARP inhibitor (PARPi) talazoparib may potentiate activity of chemotherapy and toxicity in cells vulnerable to DNA damage.Experimental Design: This phase I study evaluated the safety, tolerability, pharmacokinetics, and efficacy of talazoparib and carboplatin. Pharmacokinetic modeling explored associations between DNA vulnerability and hematologic toxicity.Results: Twenty-four patients (eight males; 16 females) with solid tumors were enrolled in four cohorts at 0.75 and 1 mg daily talazoparib and weekly carboplatin (AUC 1 and 1.5, every 2 weeks or every 3 weeks), including 14 patients (58%) with prior platinum treatment. Dose-limiting toxicities included grade 3 fatigue and grade 4 thrombocytopenia; the MTD was not reached. Grade 3/4 toxicities included fatigue (13%), neutropenia (63%), thrombocytopenia (29%), and anemia (38%). After cycle 2's dose, delays/reductions were required in all patients. One complete and two partial responses occurred in germline BRCA1/2 (gBRCA1/2) patients. Four patients showed stable disease beyond 4 months, three of which had known mutations in DNA repair pathways. Pharmacokinetic toxicity modeling suggests that after three cycles of carboplatin AUC 1.5 every 3 weeks and talazoparib 1 mg daily, neutrophil counts decreased 78% [confidence interval (CI), 87-68] from baseline in gBRCA carriers and 63% (CI, 72-55) in noncarriers (P < 0.001). Pharmacokinetic toxicity modeling suggests an intermittent, pulse dosing schedule of PARP inhibition, differentiated by gBRCA mutation status, may improve the benefit/risk ratio of combination therapy.Conclusions: Carboplatin and talazoparib showed efficacy in DNA damage mutation carriers, but hematologic toxicity was more pronounced in gBRCA carriers. Carboplatin is best combined with intermittent talazoparib dosing differentiated by germline and somatic DNA damage mutation carriers. Clin Cancer Res; 23(21); 6400-10. ©2017 AACR.

Exploring the Clinical Benefit of Docetaxel or Enzalutamide After Disease Progression During Abiraterone Acetate and Prednisone Treatment in Men With Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: Abiraterone acetate (AA) has demonstrated improved outcomes in men with metastatic castration-resistant prostate cancer (mCRPC). However, data are lacking on the effect of AA on subsequent efficacy of enzalutamide or docetaxel. PATIENTS AND METHODS: We included men with mCRPC who received AA and subsequent enzalutamide or docetaxel by August 12, 2013. Patients were separated into 3 groups: group A, treated with AA then enzalutamide before chemotherapy; group B, treated with AA then docetaxel; and group C, treated with AA and enzalutamide after chemotherapy. The primary objective was to describe the response and overall survival with subsequent therapy. RESULTS: There were 28 evaluable patients who received enzalutamide after AA (9 in group A and 19 in group C) and 13 patients who received docetaxel after AA (group B). Group A patients had more visceral disease and higher baseline prostate-specific antigen (PSA) levels, and group C men had a higher level of pain and multiple poor prognostic features. Median progression-free survival was 3.6, 5.1, and 2.8 months, respectively, and median overall survival was 8.5, not reached, and 9.6 months, respectively. A ≥ 50% PSA decline was achieved in 11%, 63%, and 5% of group A, B, and C patients, respectively. Radiographic or clinical progression as best response was noted in 55.5%, 30.8%, and 68.4% in each respective group. CONCLUSION: In this chart review of consecutive men with progressive mCRPC after AA, we found modest activity for enzalutamide and docetaxel, with clear cross-resistance for AA and enzalutamide. These data might inform the complex treatment decisions after AA treatment.

Suppression of the nitric oxide pathway in metastatic renal cell carcinoma patients receiving vascular endothelial growth factor-signaling inhibitors.

Therapies that target the vascular endothelial growth factor (VEGF) pathway cause hypertension, but the mechanism remains unknown. This cross-sectional study tested the hypothesis that VEGF inhibition causes hypertension by suppressing VEGF-mediated vasodilatory pathways. Urine was collected from 80 patients with metastatic renal cell carcinoma from 2002 to 2009, 40 at baseline and 40 while on VEGF inhibitors. Measured urinary biomarkers include albumin, metabolites of the nitric oxide (NO) pathway and its downstream effector cGMP, and prostaglandin pathway biomarkers prostaglandin E2, 6-keto prostaglandin F1α, and cAMP, all normalized to urinary creatinine. The mean age in both groups was 61.8 years, 76% were men, and urinary albumin was higher in patients receiving VEGF inhibitors (median: 18.4 versus 4.6 mg/g; P = 0.009). cGMP/creatinine was suppressed in patients on VEGF inhibitors (0.28 versus 0.39 pmol/µg; P = 0.01), with a trend toward suppression of nitrate/creatinine (0.46 versus 0.62 µmol/mg; P = 0.09). Both comparisons were strengthened when patients on bevacizumab were excluded, and only those receiving small molecule tyrosine kinase inhibitors were analyzed (cGMP/creatinine: P = 0.003; nitrate/creatinine: P = 0.01). Prostaglandin E2, 6-keto prostaglandin F1α, and cAMP did not differ between groups. These results suggest that hypertension induced by VEGF inhibitors is mediated by suppression of NO production. Prospective studies are needed to explore whether these biomarkers may be useful predictors of efficacy in patients receiving VEGF-targeted therapies.