A Phase II Study of PX-866 in Patients With Recurrent or Metastatic Castration-resistant Prostate Cancer: Canadian Cancer Trials Group Study IND205.
Clin Genitourin Cancer
; 17(3): 201-208.e1, 2019 06.
Article
in En
| MEDLINE
| ID: mdl-31056399
ABSTRACT
BACKGROUND:
In PTEN-loss models, the phosphatidylinositol 3-kinase (PI3K)/AKT and androgen receptor signaling pathways cross-regulate by reciprocal feedback whereby inhibition of one activates the other, creating a rationale for co-targeting. We studied the irreversible, pan-isoform inhibitor of Class I PI-3K PX-866 singly (part A) and with abiraterone acetate (AA) in patients on AA with rising prostate-specific antigen (PSA) (part B). PATIENTS ANDMETHODS:
The primary endpoint was lack of progression at 12 weeks. Exploratory endpoints included changes in circulating tumor cells (CTC), pharmacodynamic studies on platelets (part A), and archival tumor exploration of PTEN as predictor of response (part B).RESULTS:
A total of 43 and 25 patients accrued to parts A and B, respectively. In part A, 14 (33%) patients were progression-free at 12 weeks, with 2 partial objective responses and 1 confirmed PSA response. Favorable CTC conversion (< 5 CTC/7.5 mL) occurred in 6 (24%) of 25 evaluable patients. In part B, 11 of 25 patients had measurable disease. Six (24%) patients were progression-free at 12 weeks. No objective or PSA responses were observed. For all 68 patients, the most common toxicities were diarrhea (53 patients), nausea (36), anorexia (24), fatigue (22), and vomiting (20). Among 17 patients for whom PTEN testing was possible, 3 had PTEN homozygous deletion and 14 had no change. No correlation between PTEN status and response was seen.CONCLUSIONS:
PX-866 had modest single agent activity. Adding AA to PX-866 showed no evidence of resistance reversal. Strategies to combine PI3K inhibition with androgen receptor-targeted therapies could consider initiation earlier, combination with other agents, and/or recruiting a selected population.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
PTEN Phosphohydrolase
/
Prostatic Neoplasms, Castration-Resistant
/
Gonanes
/
Androstenes
/
Neoplasm Recurrence, Local
Type of study:
Prognostic_studies
Limits:
Aged
/
Aged80
/
Humans
/
Male
/
Middle aged
Country/Region as subject:
America do norte
Language:
En
Journal:
Clin Genitourin Cancer
Journal subject:
NEOPLASIAS
/
UROLOGIA
Year:
2019
Type:
Article