First-line talazoparib with enzalutamide in HRR-deficient metastatic castration-resistant prostate cancer: the phase 3 TALAPRO-2 trial.

Preclinical evidence has suggested an interplay between the androgen receptor, which largely drives the growth of prostate cancer cells, and poly(ADP-ribose) polymerase. This association provides a rationale for their co-inhibition for the treatment of metastatic castration-resistant prostate cancer (mCRPC), an area of unmet medical need. The phase 3 TALAPRO-2 study investigated combining the poly(ADP-ribose) polymerase inhibitor talazoparib with enzalutamide versus enzalutamide alone as first-line treatment of mCRPC. Patients were prospectively assessed for tumor alterations in DNA damage response genes involved in homologous recombination repair (HRR). Two cohorts were enrolled sequentially: an all-comers cohort that was enrolled first (cohort 1; N = 805 (169 were HRR-deficient)), followed by an HRR-deficient-only cohort (cohort 2; N = 230). We present results from the alpha-controlled primary analysis for the combined HRR-deficient population (N = 399). Patients were randomized in a 1:1 ratio to talazoparib or placebo, plus enzalutamide. The primary endpoint, radiographic progression-free survival, was met (median not reached at the time of the analysis for the talazoparib group versus 13.8 months for the placebo group; hazard ratio, 0.45; 95% confidence interval, 0.33 to 0.61; P < 0.0001). Data for overall survival, a key secondary endpoint, are immature but favor talazoparib (hazard ratio, 0.69; 95% confidence interval, 0.46 to 1.03; P = 0.07). Common adverse events in the talazoparib group were anemia, fatigue and neutropenia. Combining talazoparib with enzalutamide significantly improved radiographic progression-free survival in patients with mCRPC harboring HRR gene alterations, supporting talazoparib plus enzalutamide as a potential first-line treatment for these patients. ClinicalTrials.gov Identifier: NCT03395197 .

Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Co-inhibition of poly(ADP-ribose) polymerase (PARP) and androgen receptor activity might result in antitumour efficacy irrespective of alterations in DNA damage repair genes involved in homologous recombination repair (HRR). We aimed to compare the efficacy and safety of talazoparib (a PARP inhibitor) plus enzalutamide (an androgen receptor blocker) versus enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: TALAPRO-2 is a randomised, double-blind, phase 3 trial of talazoparib plus enzalutamide versus placebo plus enzalutamide as first-line therapy in men (age ≥18 years [≥20 years in Japan]) with asymptomatic or mildly symptomatic mCRPC receiving ongoing androgen deprivation therapy. Patients were enrolled from 223 hospitals, cancer centres, and medical centres in 26 countries in North America, Europe, Israel, South America, South Africa, and the Asia-Pacific region. Patients were prospectively assessed for HRR gene alterations in tumour tissue and randomly assigned (1:1) to talazoparib 0·5 mg or placebo, plus enzalutamide 160 mg, administered orally once daily. Randomisation was stratified by HRR gene alteration status (deficient vs non-deficient or unknown) and previous treatment with life-prolonging therapy (docetaxel or abiraterone, or both: yes vs no) in the castration-sensitive setting. The sponsor, patients, and investigators were masked to talazoparib or placebo, while enzalutamide was open-label. The primary endpoint was radiographic progression-free survival (rPFS) by blinded independent central review, evaluated in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT03395197) and is ongoing. FINDINGS: Between Jan 7, 2019, and Sept 17, 2020, 805 patients were enrolled and randomly assigned (402 to the talazoparib group and 403 to the placebo group). Median follow-up for rPFS was 24·9 months (IQR 21·9-30·2) for the talazoparib group and 24·6 months (14·4-30·2) for the placebo group. At the planned primary analysis, median rPFS was not reached (95% CI 27·5 months-not reached) for talazoparib plus enzalutamide and 21·9 months (16·6-25·1) for placebo plus enzalutamide (hazard ratio 0·63; 95% CI 0·51-0·78; p<0·0001). In the talazoparib group, the most common treatment-emergent adverse events were anaemia, neutropenia, and fatigue; the most common grade 3-4 event was anaemia (185 [46%] of 398 patients), which improved after dose reduction, and only 33 (8%) of 398 patients discontinued talazoparib due to anaemia. Treatment-related deaths occurred in no patients in the talazoparib group and two patients (<1%) in the placebo group. INTERPRETATION: Talazoparib plus enzalutamide resulted in clinically meaningful and statistically significant improvement in rPFS versus standard of care enzalutamide as first-line treatment for patients with mCRPC. Final overall survival data and additional long-term safety follow-up will further clarify the clinical benefit of the treatment combination in patients with and without tumour HRR gene alterations. FUNDING: Pfizer.

Talazoparib, a Poly(ADP-ribose) Polymerase Inhibitor, for Metastatic Castration-resistant Prostate Cancer and DNA Damage Response Alterations: TALAPRO-1 Safety Analyses.

BACKGROUND: The phase II TALAPRO-1 study (NCT03148795) demonstrated durable antitumor activity in men with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC). Here, we detail the safety profile of talazoparib. PATIENTS AND METHODS: Men received talazoparib 1 mg/day (moderate renal impairment 0.75 mg/day) orally until radiographic progression, unacceptable toxicity, investigator decision, consent withdrawal, or death. Adverse events (AEs) were evaluated: incidence, severity, timing, duration, potential overlap of selected AEs, dose modifications/discontinuations due to AEs, and new clinically significant changes in laboratory values and vital signs. RESULTS: In the safety population (N = 127; median age 69.0 years), 95.3% (121/127) experienced all-cause treatment-emergent adverse events (TEAEs). Most common were anemia (48.8% [62/127]), nausea (33.1% [42/127]), decreased appetite (28.3% [36/127]), and asthenia (23.6% [30/127]). Nonhematologic TEAEs were generally grades 1 and 2. No grade 5 TEAEs or deaths were treatment-related. Hematologic TEAEs typically occurred during the first 4-5 months of treatment. The median duration of grade 3-4 anemia, neutropenia, and thrombocytopenia was limited to 7-12 days. No grade 4 events of anemia or neutropenia occurred. Neither BRCA status nor alteration origin significantly impacted the safety profile. The median (range) treatment duration was 6.1 (0.4-24.9) months; treatment duration did not impact the incidence of anemia. Only 3 of the 15 (11.8% [15/127]) permanent treatment discontinuations were due to hematologic TEAEs (thrombocytopenia 1.6% [2/127]; leukopenia 0.8% [1/127]). CONCLUSION: Common TEAEs associated with talazoparib could be managed through dose modifications/supportive care. Demonstrated efficacy and a manageable safety profile support continued evaluation of talazoparib in mCRPC. CLINICALTRIALS.GOV IDENTIFIER: NCT03148795.

Performance of sentinel lymph node biopsy in high-risk endometrial cancer.

OBJECTIVE: To determine the rate and performance of sentinel lymph node (SLN) mapping among women with high-risk endometrial cancers. METHODS: Patients diagnosed between 2012 and 2015 with uterine cancer of grade 3 endometrioid, clear cell, serous or carcinosarcoma histology and who underwent SLN mapping prior to full pelvic lymph node dissection were included. Subjects underwent methylene blue or ICG injection for laparoscopic (N = 16) or robotic-assisted laparoscopic (N = 20) staging. Outcomes included SLN mapping rates, SLN and non-SLN positive rates, false negative SLN algorithm rate, and the negative predictive value (NPV) of the SLN algorithm. Fisher's exact test was used to compare mapping and node positivity rates. RESULTS: 9/36 (25%) patients with high-risk uterine cancer had at least one metastatic lymph node identified. Successful mapping occurred in 30/36 (83%) patients. SLN mapped to pelvic nodes bilaterally in 20 (56%), unilaterally in 9 (25%), and aortic nodes only in 1 (3%). Malignancy was identified in 14/95 (15%) of all sentinel nodes and 12/775 (1.5%) of all non-sentinel nodes (p < 0.001). The false negative rate of SLN mapping alone was 2/26 (7.7%); the NPV was 92.3%. When the SLN algorithm was applied retrospectively the false negative rate was 0/31 (0%); the NPV was 100%. CONCLUSION: SLN mapping rates for high-risk cancers are slightly lower than in prior reports of lower risk cancers. The NPV of the SLN mapping alone is 92% and rises to 100% when the SLN algorithm is applied. Such results are acceptable and consistent with larger subsets of lower risk endometrial cancers.

Postoperative Pain Scores and Narcotic Use in Robotic-assisted Versus Laparoscopic Hysterectomy for Endometrial Cancer Staging.

STUDY OBJECTIVE: To retrospectively evaluate perioperative pain and analgesic and antiemetic use in patients who underwent surgical staging for endometrial cancer using traditional versus robotic-assisted laparoscopy. DESIGN: We identified women in a single institution who underwent minimally hysterectomy for endometrial cancer from 2008 to 2012. Patient characteristics and perioperative outcomes, including analgesic and antiemetic use and pain scores, were analyzed. After univariate analysis, a multivariate linear regression model was generated to determine factors associated with narcotic use in the post anesthesia care unit (PACU) (Canadian Task Force Classification II-3). SETTING: A single academic institution in the United States from 2008 to 2012. PATIENTS: Women undergoing total laparoscopic hysterectomy or robotic-assisted laparoscopic hysterectomy for endometrial cancer. INTERVENTIONS: Laparoscopic or robotic-assisted laparoscopic hysterectomy. MEASUREMENTS AND MAIN RESULTS: Three hundred thirty-five women were included (213 laparoscopy and 122 robotic-assisted laparoscopy). There was no difference in pain scores at 0 to 6 and 6 to 12 hours after surgery; at 12 to 24 hours, robotic-assisted surgery was associated with higher median pain scores (5/10 vs 4/10, p = .012). Robotic-assisted surgery was associated with a longer anesthesia time (289 vs 255 minutes, p < .001), similar antiemetic use (p = .40), and lower narcotic use in the postanesthesia care unit (PACU) (1.3 mg vs 2.5 mg morphine equivalents, p = .003). There was no difference in narcotic use on the postoperative floor (p = .46). In multivariate analysis controlling for age, menopausal status, anesthesia duration, and local anesthetic use, hysterectomy type was not a significant predictor of PACU narcotic use (p = .86). CONCLUSIONS: In a retrospective analysis, a robotic-assisted approach to endometrial cancer was not associated with reduced PACU narcotic or antiemetic use compared with the traditional laparoscopic approach. Twenty-four-hour narcotic and antiemetic use was also not different between the 2 approaches.

Relationship between minimally invasive hysterectomy, pelvic cytology, and lymph vascular space invasion: a single institution study of 458 patients.

OBJECTIVE: The aim of this study is to determine whether a minimally invasive approach to hysterectomy is associated with an increased rate of lymph vascular space invasion (LVSI) and/or malignant pelvic peritoneal cytology in endometrial cancer. METHODS: We performed a single institution analysis of 458 women with endometrial cancer who underwent either total abdominal hysterectomy (TAH) or minimally invasive hysterectomy (MIH) with use of a disposable uterine manipulator. All patients had endometrial cancer diagnosed by endometrial biopsy at a single academic institution between 2002 and 2012. Exclusion criteria were pre-operative D&C and/or hysteroscopy, uterine perforation or morcellation, and conversion to laparotomy. Multivariate logistic regression models to determine if type of hysterectomy predicts either LVSI or presence of abnormal cytology were controlled for grade, stage, depth of invasion, tumor size, cervical and adnexal involvement. RESULTS: LVSI was identified in 39/214 (18%) MIH and 44/242 (18%) TAH (p=0.99). Pelvic washings were malignant in 14/203 (7%) MIH and 16/241 (7%) TAH (p=1.0). Washings were atypical or inconclusive in 16/203 (8%) MIH and 6/241 (2.5%) TAH (p=0.014). In multivariate analyses, type of hysterectomy was not a significant predictor of either LVSI (p=0.29) or presence of malignant washings (p=0.66), but was a predictor of atypical or inconclusive washings (p=0.03). CONCLUSION: Minimally invasive hysterectomy with use of a uterine manipulator for endometrial cancer is not associated with LVSI or malignant cytology. Algorithms that better determine the etiology and implications of inconclusive or atypical pelvic cytology are needed to inform the possible additional risk associated with a minimally invasive approach to endometrial cancer.

A functional perspective of nitazoxanide as a potential anticancer drug.

Cancer is a group of diseases characterized by uncontrolled cell proliferation, evasion of cell death and the ability to invade and disrupt vital tissue function. The classic model of carcinogenesis describes successive clonal expansion driven by the accumulation of mutations that eliminate restraints on proliferation and cell survival. It has been proposed that during cancer's development, the loose-knit colonies of only partially differentiated cells display some unicellular/prokaryotic behavior reminiscent of robust ancient life forms. The seeming "regression" of cancer cells involves changes within metabolic machinery and survival strategies. This atavist change in physiology enables cancer cells to behave as selfish "neo-endo-parasites" that exploit the tumor stromal cells in order to extract nutrients from the surrounding microenvironment. In this framework, it is conceivable that anti-parasitic compounds might serve as promising anticancer drugs. Nitazoxanide (NTZ), a thiazolide compound, has shown antimicrobial properties against anaerobic bacteria, as well as against helminths and protozoa. NTZ has also been successfully used to promote Hepatitis C virus (HCV) elimination by improving interferon signaling and promoting autophagy. More compelling however are the potential anti-cancer properties that have been observed. NTZ seems to be able to interfere with crucial metabolic and pro-death signaling such as drug detoxification, unfolded protein response (UPR), autophagy, anti-cytokine activities and c-Myc inhibition. In this article, we review the ability of NTZ to interfere with integrated survival mechanisms of cancer cells and propose that this compound might be a potent addition to the current chemotherapeutic strategy against cancer.

Research perspective: potential role of nitazoxanide in ovarian cancer treatment. Old drug, new purpose?

Among gynecological malignancies epithelial ovarian cancer (EOC) is the leading cause of death. Despite improvements in conventional chemotherapy combinations, the overall cure rate has remained mostly stable over the years, and only 10%-15% of patients maintain a complete response following first-line therapy. To improve the efficacy of ovarian cancer chemotherapy it is essential to develop drugs with new mechanisms of action. Compared to normal tissues, protein disulfide isomerase (PDI) is overexpressed in ovarian tumors. PDI is a cellular enzyme in the lumen of the endoplasmic reticulum (ER) of eukaryotes or the periplasmic region of prokaryotes. This protein catalyzes the formation and breakage of disulphide bonds between cysteine residues in proteins, which affects protein folding. Selective inhibition of PDI activity has been exhibited both in vitro and in vivo anticancer activity in human ovarian cancer models. PDI inhibition caused accumulation of unfolded or misfolded proteins, which led to ER stress and the unfolded protein response (UPR), and in turn resulted in cell death. Nitazoxanide [NTZ: 2-acetyloxy-N-(5-nitro-2-thiazolyl)benzamide] is a thiazolide antiparasitic agent with excellent activity against a wide variety of protozoa and helminths. In this article, we propose that NTZ, acting as PDI inhibitor, may be a new and potent addition to the chemotherapeutic strategy against ovarian cancer.

Beyond mere obesity: effect of increasing obesity classifications on hysterectomy outcomes for uterine cancer/hyperplasia.

OBJECTIVE: To assess the impact of obesity severity on hysterectomy outcomes for uterine hyperplasia/cancer. METHODS: The data from women undergoing hysterectomies for endometrial hyperplasia/uterine cancer with a BMI≥30 kg/m(2) were abstracted from records at the University of Virginia and Duke University following IRB approval. Univariate and multivariate statistical analyses were performed. RESULTS: Mean age of the 659 patients was 58.1 yrs; mean body mass index (BMI) was 43 kg/m(2). Women were grouped based on BMI: 39.6% (261) were obese (30-39 kg/m(2)), 41.7% (275) were morbidly obese (40-49 kg/m(2)) and 18.7% (123) were super obese (≥50 kg/m(2)). Minimally invasive surgical procedures (MIS) were attempted in 280 patients with a conversion rate of 16.1%; BMI was higher in the converted group (47.3 vs. 40.6 kg/m(2); p<0.001). As obesity group increased, there was a decreased frequency of lymphadenectomy (63.8% vs. 37.1% vs. 20.3%; p<0.001), increased blood loss (242 vs. 281 vs. 378 mL; p<0.001) and fewer nodes removed (p<0.001). On multivariate analysis, type of surgery (open vs. MIS) and obesity classification were independently and significantly associated with wound complications (p<0.001) and the presence of postoperative complications (p<0.001, p=0.003). Surgical staging with lymphadenectomy was significantly associated with obesity (p<0.001) but not procedure type (p=0.11). Blood transfusion (p<0.001), hospital readmission (p=0.025), and ileus (p<0.001) were significantly associated with open procedures but not obesity. There were no significant differences in progression-free or disease-specific survival based on obesity group. CONCLUSION: Women with BMI's exceeding 40 kg/m(2) have worse surgical outcomes than their less obese counterparts.

Retrospective review of an intraoperative algorithm to predict lymph node metastasis in low-grade endometrial adenocarcinoma.

OBJECTIVE: To validate the Mayo algorithm to intraoperatively identify women with endometrial cancer in whom lymphadenectomy may be safely omitted. METHODS: A multi-center retrospective chart review 1977-2010 was completed using two independent institutional endometrial cancer databases. Eligibility criteria were grade 1 or 2 endometrial carcinoma, low-risk histology, and myometrial invasion ≤ 50% on intraoperative pathology consultation; patients were considered to satisfy the Mayo criteria if, in addition to these, tumor diameter on the final pathology report was ≤ 2 cm. Analysis of nodal metastases, recurrent disease, and progression-free survival (PFS) using the Kaplan-Meier method was performed. RESULTS: Six hundred and two patients met inclusion criteria for the study. Of 110 patients satisfying the Mayo algorithm with an adequate lymphadenectomy, 2 (1.8%) were diagnosed with lymph node metastasis and 4 (3.6%) subsequently developed recurrent disease. The Mayo algorithm identified with a 98.2% negative predictive value women who would not benefit from a lymphadenectomy. There was no significant difference in recurrence rate or PFS between women who underwent lymphadenectomy and those who did not when the Mayo algorithm was satisfied. CONCLUSIONS: The Mayo algorithm intraoperatively identifies tumor characteristics of low-risk disease in endometrial carcinoma that predict a very low likelihood of nodal metastasis and recurrence. Although a small number of patients with advanced stage disease may be missed when applying the Mayo criteria, there is no apparent survival benefit to lymphadenectomy for patients satisfying this algorithm, and these data support its use at other institutions.