Clin Cancer Res: A Phase I study of Niraparib in combination with radium-223 in metastatic castration-resistant prostate cancer

An estimated 250,000 men in the United States were diagnosed with prostate cancer in 2021, making it the second leading cause
of cancer death among men in the United States.
The growth of prostate cancer cells depends on male hormones, so male hormone blocking therapy is the basic treatment for
prostate cancer.
But over time, the therapy still progresses to the disease, in part through mechanisms that do not rely on male hormone stimulation to reactivate, causing castration-resistant prostate cancer
.

Researchers from the United States recently published an article in Clin Cancer Res investigating the safety profile of niraparib, a PARP inhibitor, in combination with Radium-223 for metastasis-resistant prostate cancer (mCRPC
).

Studies included men
who developed progressive mCPRC and bone metastases after receiving ≥1-line androgen receptor (AR)-targeted therapy but no known BRCA-1 or BRCA-2 variants or larger visceral disease.
Niraparib doses were escalated and used in combination with the standard dose of Radium-223 and evaluated
using a time-event continuous reassessment.
The highest dose level < 20% of the dose-limit toxicity (DLT) probability is defined as the maximum tolerated dose (MTD).

Secondary endpoints included PSA change and progression-free survival
.
Exploratory analysis includes evaluation of DNA mutations found in ctDNA as well as gene expression changes
assessed in whole blood samples.

A total of 30 patients were treated
with niraparib and radium-223.
Of these, 13 patients were treated with 100 mg of niraparib, 12 patients were treated with 200 mg of niraparib, and 5 patients were treated
with 300 mg of niraparib.
There were 6 DLT events: 2 (13%) neutropenia, 2 (13%) thrombocytopenia, fatigue and nausea 1 (3%)
.
Anaemia (2/13%) and neutropenia (2/13%) were the most common grade 3 adverse events
.
For patients who have received prior chemotherapy, the MTD is 100 mg, compared with 200 mg
for patients who have not received chemotherapy.
Whole blood PAX5 and CD19 genes were higher in responders, while ARG-1, IL-2R, and FLT3 genes were higher
in non-responders.

Radiological progression-free survival (rPFS) condition

In summary, niraparib in combination with Radium-223 is safe
in patients with mCRPC.
In addition, further studies combined with biomarkers will better elucidate the effects of
PARP inhibitors in combination therapy with DNA-damaging drugs and other drugs.

Original source:

Zachary Quinn， Benjamin Leiby， Guru Sonpavde et al.
Phase I Study of Niraparib in Combination with Radium-223 for the Treatment of Metastatic Castrate Resistant Prostate Cancer .
Clin Cancer Res.
Nov 2022