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Although androgen receptor-targeted agents prolong the lives of patients with metastatic prostate cancer, patients develop therapy resistance and most ultimately succumb to the disease. The PI3K/AKT/PTEN pathway has been associated with the development of resistance, raising the possibility that pathway inhibitors may produce a clinical benefit. This open-label phase Ib study examined the safety, tolerability, pharmacokinetics (PK) and preliminary clinical activity of adding capivasertib - a potent, selective inhibitor of AKT1/2/3 - to approved abiraterone acetate therapy.Twenty-seven patients with metastatic castration-resistant prostate cancer who had undergone at least 1 prior line of systemic therapy received abiraterone acetate 1000 mg (orally administered once daily), plus oral prednisone 5 mg (twice daily) with capivasertib 400 mg (orally, twice daily, with an intermittent schedule of 4 days on, 3 days off).No dose-limiting toxicity was observed. The most frequent adverse events (all grade) were diarrhea (30%), anemia (26%), asthenia (22%), and nausea (22%). The most frequent grade 3 or higher adverse events were acute kidney injury (19%), hyperglycemia (7%), rash (7%), abdominal pain (7%), and asthenia (7%). Capivasertib and abiraterone PK were consistent with previously reported results from monotherapy dosing. Nine participants (33%) showed a 20% or greater decrease in prostate-specific antigen during study treatment.The combination of capivasertib and abiraterone acetate had an acceptable tolerability profile consistent with the known profile of each agent. These data support further evaluation of capivasertib and abiraterone acetate in patients with advanced prostate cancer.

Active germ cell malignancies express high levels of specific circulating micro-RNAs (miRNAs), including miR-371a-3p (miR371), which is undetectable in teratoma. Teratoma markers are urgently needed for theselection of patients and treatments because of the risk of malignant transformation and growing teratoma syndrome. To assess the accuracy of plasma miR375 alone or in combination with miR371 in detecting teratoma, 100 germ cell tumor patients, divided into two cohorts, were enrolled in a prospective multi-institutional study. In the discovery cohort, patients with pure teratoma and with no/low risk of harboring teratoma were compared; the validation cohort included patients with confirmed teratoma, active germ cell malignancy, or complete response after chemotherapy. The area under the receiver operating characteristic curve values for miR375, miR371, and miR371-miR375 were, respectively, 0.93 (95% confidence interval [CI]: 0.87-0.99), 0.59 (95% CI: 0.44-0.73), and 0.95 (95% CI: 0.90-0.99) in the discovery cohort and 0.55 (95% CI: 0.36-0.74), 0.74 (95% CI: 0.58-0.91), and 0.77 (95% CI: 0.62-0.93) in the validation cohort. Our study demonstrated that the plasma miR371-miR375 integrated evaluation is highly accurate to detect teratoma. PATIENT SUMMARY: The evaluation of two micro-RNAs (miR375-miR371) in the blood of patients with germ cell tumors is promising to predict teratoma. This test could be particularly relevant to the identification of teratoma in patients with postchemotherapy residual disease. info:eu-repo/semantics/publishedVersion

Germ cell tumors (GCT) are the most common cancer in men between 15 and 35 years of age and the incidence has increased during the past several decades. This article reviews the current knowledge on high-dose chemotherapy (HDCT) and stem cell transplant for salvage treatment of patients with relapsed metastatic GCT. Furthermore, the authors attempt to dissect the controversy of using standard-dose versus high-dose therapy as initial salvage and identify patients who are most likely to benefit from HDCT and peripheral blood stem cell transplant.

The therapeutic benefit of performing a lymph node dissection (LND) in patients with renal cell carcinoma (RCC) has been controversial. In prior studies, it was thought that a low event rate for nodal metastases affected the ability to draw any conclusions. Here, we opted to select patients that had low burden 1 or 2 nodes positive to study survival outcomes and recurrence patterns based on limited LND or extended LND with a template retroperitoneal lymph node dissection (RPLND).We used our single institutional database from 2000 and 2019 and identified 45 patients that had only 1 or 2 nodes positive on final pathology without any other systemic disease. These patients all underwent nephrectomy with limited LND or a template RPLND on the ipsilateral side.We identified 23 patients in the limited LND and 22 in the template RPLND group. Thirty-one patients included in the study had 1 positive lymph node and 14 patients had 2 positive lymph nodes. For patients undergoing a limited LND, a median 4 (IQR 1-11) lymph nodes were resected and for those undergoing template RPLND, 18 (IQR: 13-23) lymph nodes were resected. On Kaplan-Meier analysis, a difference was noted in overall survival (P = 0.04) when comparing limited LND to template RPLND. We also mapped out patterns of recurrence and found that 6 patients had retroperitoneal lymph node recurrences after a limited LND in the ipsilateral node packet. On univariate analysis, pathologic stage was a major factor for survival, but did not remain as significant with the inclusion of template RPLND status and Charlson Comorbidity Index in multivariate analysis.We identified specific patients that had RCC with limited lymph node involvement. We found that a select number of patients had durable improvement in survival outcomes with template RPLND. In examining the recurrence patterns, a greater number of patients may have derived benefit for an initial template RPLND.

Background To report our experience utilizing a multidisciplinary clinic (MDC) at Indiana University (IU) since the publication of the International Germ Cell Cancer Collaborative Group (IGCCCG), and to compare our overall survival (OS) to that of the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program. Patients and methods We conducted a retrospective analysis of all patients with metastatic germ-cell tumor (GCT) seen at IU from 1998 to 2014. A total of 1611 consecutive patients were identified, of whom 704 patients received an initial evaluation by our MDC (including medical oncology, pathology, urology and thoracic surgery) and started first-line chemotherapy at IU. These 704 patients were eligible for analysis. All patients in this cohort were treated with cisplatin–etoposide-based combination chemotherapy. We compared the progression-free survival (PFS) and OS of patients treated at IU with that of the published IGCCCG cohort. OS of the IU testis cancer primary cohort (n = 622) was further compared with the SEER data of 1283 patients labeled with ‘distant' disease. The Kaplan–Meier method was used to estimate PFS and OS. Results With a median follow-up of 4.4 years, patients with good, intermediate, and poor risk disease by IGCCCG criteria treated at IU had 5-year PFS of 90%, 84%, and 54% and 5-year OS of 97%, 92%, and 73%, respectively. The 5-year PFS for all patients in the IU cohort was 79% [95% confidence interval (CI) 76% to 82%]. The 5-year OS for the IU cohort was 90% (95% CI 87% to 92%). IU testis cohort had 5-year OS 94% (95% CI 91% to 96%) versus 75% (95% CI 73% to 78%) for the SEER ‘distant' cohort between 2000 and 2014, P-value Conclusion The MDC approach to GCT at high-volume cancer center associated with improved OS outcomes in this contemporary dataset. OS is significantly higher in the IU cohort compared with the IGCCCG and SEER ‘distant' cohort.

Background Despite remarkable results with salvage standard-dose or high-dose chemotherapy ~15% of patients with relapsed germ-cell tumors (GCT) are incurable. Immune checkpoint inhibitors have produced significant remission in multiple tumor types. We report the first study of immunotherapy in patients with GCT. Patients and methods Single arm phase II trial investigating pembrolizumab 200 mg i.v. Q3weeks until disease progression in patients with relapsed GCT and no curable options. Patients age ≥18 with GCT who progressed after first-line cisplatin-based chemotherapy and after at least one salvage regimen (high-dose or standard-dose chemotherapy) were eligible. Centrally assessed programmed death-ligand 1 (PD-L1) on tumor and infiltrating immune cells was scored. Primary end point was overall response rate using immune-related response criteria. Simon two-stage design with type I error 20% and power 80% was utilized. Results Twelve male patients were enrolled. Median age was 38 years. All patients had nonseminoma. Primary site was testis (11) or mediastinum (1). Median AFP 615 (range 1–32, 760) and hCG 4 (range 0.6–37, 096). Six patients had late relapse (>2 years). Median number of previous chemotherapy regimens was 3. Six patients received prior high-dose chemotherapy. Two patients had positive PD-L1 staining (H-score 90 and 170). Median number of pembrolizumab doses was 2 (range 1–8). There were six grade 3 adverse events. No immune-related adverse events were reported. No partial or complete responses were observed. Two patients achieved radiographic stable disease for 28 and 19 weeks, respectively; both had continued rising AFP level despite radiographic stability and had negative PD-L1 staining. Conclusion This is the first reported trial evaluating immune checkpoint inhibitors in GCT. Pembrolizumab is well tolerated but does not appear to have clinically meaningful single-agent activity in refractory GCT. Clinical trial information NCT02499952.

Background Although once considered a homologous recombination DNA repair gene, CDK12 is now thought to have a distinct role in maintaining genomic stability. In prostate cancer, inactivating CDK12 mutations lead to gene fusion-induced neoantigens and possibly sensitivity to PD1 inhibitors. Methods We conducted a retrospective multicenter study to identify advanced prostate cancer patients with loss-of-function CDK12 mutations. We characterized their clinical features and therapeutic outcomes, including sensitivity to PARP and PD1 inhibitors. Results 58 men with at least monoallelic CDK12 alterations were identified from 9 academic centers; 28 (48%) had biallelic inactivation. Tissue for genomics was from primary tumors in 45 cases (77%) and from metastatic sites in 13 cases (23%). All CDK12 mutations were somatic-only. Median age at diagnosis was 60 y (41–78 y), 71%/29% were white/nonwhite, 79% had Gleason sum 9-10, 10% had ductal/intraductal histology, 76% had stage T3/T4 disease, 47% had metastases at diagnosis, and the median PSA was 24 ng/mL. Of those undergoing primary ADT (± Abi, ± Doce) for advanced disease (n = 54), only 85% had a PSA50 response, with median PFS of 11.8 (95% CI 8.3–15.4) mo; OS from ADT initiation was 40.8 (95% CI 18.7–53) mo. Of those receiving first-line Abi/Enza for mCRPC (n = 34), only 47% had a PSA50 response, with median PFS of 4.3 (95% CI 2.6–6.0) mo. Of those receiving a first Taxane agent for mCRPC (n = 20), only 35% had a PSA50 response, with median PFS of 4.0 (95% CI 2.6–5.3) mo. Eleven men received a PARP inhibitor (10 Olaparib, 1 Rucaparib): none had a PSA50 response, and median PFS was 3.6 (95% CI 3.0–4.2) mo. Eight men received a PD1 inhibitor as 4th to 6th-line mCRPC therapy (5 Pembro, 3 Nivo): 38% had a PSA50 response, and median PFS was 6.6 (95% CI 2.3–10.8) mo. Conclusions CDK12-altered prostate cancer is an aggressive subtype presenting at young age, with high Gleason grade, and often with de novo M1 disease at diagnosis. Outcomes to hormonal and taxane therapies are poor, and PARP inhibitors are also ineffective. A proportion of these patients respond favorably to PD1 inhibitors, implicating CDK12 deficiency in immunotherapy responsiveness. Legal entity responsible for the study Emmanuel S. Antonarakis. Funding Has not received any funding. Disclosure E.S. Antonarakis: Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Astellas; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy, Research grant / Funding (institution): Dendreon; Advisory / Consultancy, Research grant / Funding (institution): Medivation; Advisory / Consultancy: ESSA; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Clovis; Advisory / Consultancy, Research grant / Funding (institution): Merck; Research grant / Funding (institution): Johnson & Johnson; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Eli Lilly; Licensing / Royalties: Qiagen. N. Agarwal: Advisory / Consultancy: Astellas; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Argos; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Clovis; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Advisory / Consultancy, Research grant / Funding (institution): EMD Serono; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Advisory / Consultancy: Foundation One; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Medivation; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Nektar; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Bavarian Nordic; Research grant / Funding (institution): Calithera; Research grant / Funding (institution): Celldex. B.L. Maughan: Advisory / Consultancy: Peloton Therapeutics; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Tempus; Advisory / Consultancy: Bayer; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Janssen; Advisory / Consultancy: Astellas. M. Hussain: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (self), Research grant / Funding (institution): Genentech; Honoraria (self): Sanofi Genzyme; Honoraria (self): Research To Practice; Honoraria (self): Aptitude Health; Honoraria (self): Epics. All other authors have declared no conflicts of interest.