ASCO 2020: Clinical Outcomes and Markers of Treatment Response in a Randomized Phase II Study of Androgen Deprivation Therapy with or Without Palbociclib in RB-Intact Metastatic Hormone-Sensitive Prostate Cancer

( Inhibition of the cell cycle enzymes CDK4 and CDK6 are standard of care interventions in both adjuvant management of breast cancer as well as in the metastatic setting. Preclinical models of prostate cancer also suggest the importance of CDK4/6 function in the context of androgen signaling and expression of retinoblastoma (RB). In this poster, Dr. Phillip Palmbos and colleagues report results and molecular correlatives from a Phase II randomized study (NCT02059213) in patients with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) treated with androgen deprivation therapy (ADT) and antagonism of the androgen receptor (AR) with bicalutamide +/- the CDK4/6 inhibitor palbociclib. Inclusion criteria are below, and importantly, required intact expression of RB. The primary endpoint of the study was to compare the rate of prostate-specific antigen (PSA) decrease to < 4 ng/mL after 28 weeks of therapy. Secondary endpoints were safety, rate of achieving PSA < 0.2 ng/mL, and response rates such as biochemical progression-free survival and radiologic response rates. Correlative endpoints were the number of circulating tumor cells (CTCs) at baseline and on therapy as well as transcriptome and mutational assessment of tumor tissue.

androgen deprivation therapy with or without palbociclib study schema

Patient randomization resulted in treatment arms that were evenly matched for age, PSA, Eastern Cooperative Oncology Group (ECOG), Gleason score, treatment to date, and disease sites. The addition of palbociclib to ADT with Lupron® and bicalutamide did not improve the primary outcome of PSA < 4 ng/mL, and was also not associated with differences in complete PSA response or radiologic response.

PSA progression free survival

Regarding correlative studies, the authors found that pretreatment CTC counts ≥ 2/mL were associated with decreased rates of PSA response and progression-free survival.

pretreatment ctc correlated with pfs

pretreatment ctc correlated with psa response

Mutations in TP53, PIK3, and gain of chromosome 8q were significantly associated with time to PSA progression.

time to psa progression

In conclusion, no difference in PSA or clinical response was observed in this biomarker stratified randomized Phase II trial of the addition of palbociclib ADT with bicalutamide. Correlative analyses showed that higher CTC levels and certain genomic alterations associated with prostate cancer were enriched for decreased progression-free survival. Further study of CDK4/6 inhibitors with more recent androgen receptor inhibitors may still be warranted. 

Presented by: Phillip Lee Palmbos, MD, PhD, Assistant Professor, University of Michigan, Ann Arbor, Michigan

Written by: Alok Tewari, MD, PhD, Medical Oncology Fellow at the Dana-Farber Cancer Institute, Boston, Massachusetts, at the 2020 American Society of Clinical Oncology Virtual Annual Meeting (#ASCO20), May 29th-May 31st, 2020