Targeted Alpha Therapy Plus PARP Blockade: AZD2265 plus AZD9574 for Advanced Prostate Cancer

There is a new flexible trial for men with metastatic prostate cancer that has stopped responding to hormone therapy. Phase 1/2 PROSPECTOR trial tests three options: a PSMA‑targeted radioactive drug (AZD2265), the same drug combined with a PARP1 inhibitor (AZD9574), and standard docetaxel chemotherapy. The first part of the trial finds safe dose levels and main side effects, and the second part looks more closely at how well each option works, using the proportion of patients with at least a 50% drop in PSA (PSA50) as a key early measure of benefit.

AZD2265 is a PSMA‑targeted alpha therapy closely related to an actinium‑225–labeled molecule called 225Ac‑PSMA‑I&T, which has been studied in preclinical prostate cancer models. In PSMA‑positive cell lines, actinium‑225 PSMA ligands kill cancer cells very efficiently, while having little effect on PSMA‑negative cells, showing that the radiation is being delivered where it is needed. In mouse models bearing PSMA‑positive tumors, related actinium‑225 PSMA agents such as 225Ac‑PSMA‑617 have produced strong tumor control: a single treatment dose reduced tumor growth by about 75% compared with untreated controls and significantly delayed the time until tumors reached a defined size, without causing major kidney damage.

AZD9574 is an oral PARP1 inhibitor designed to block one of the main DNA repair pathways that cancer cells use to recover from damage. In laboratory tests it shuts down PARP1 activity at very low concentrations (around 0.3–2 nanomoles) and is more than 8000 times more selective for PARP1 than for other PARP family enzymes. In cell models where the BRCA2 repair gene is switched off, AZD9574 stops cancer cell growth at roughly 1.38 nanomoles, whereas cells with normal BRCA2 need more than 40,000 nanomoles to see the same effect (about a 20,000‑fold difference) showing strong synthetic lethality when DNA repair is already weakened. In animal tumor models with BRCA1 or other DNA‑repair defects, AZD9574 has caused deep tumor regressions and long‑lasting control, and it has slowed or stopped brain tumor growth and prolonged survival, confirming that it can reach tumors and keep them under pressure over time.

The combination of AZD2265 and AZD9574 in this trial is built on these preclinical efficacy signals. The PSMA‑targeted alpha therapy delivers intense, localized DNA damage to PSMA‑positive prostate cancer cells, while AZD9574 makes it much harder for those cells to repair that damage, especially if they already carry DNA‑repair defects. Preclinical data with actinium‑225 PSMA ligands show strong tumor growth inhibition and delayed progression, and preclinical data with AZD9574 show potent, long‑lasting tumor control in repair‑deficient models, including in the brain. In the clinical platform, Part A uses this information to select doses that are likely to be active but still tolerable, and Part B then tests whether the combination can deliver higher PSA50 rates and more durable responses than AZD2265 alone or docetaxel, without causing too much bone marrow, kidney or salivary gland toxicity.

Clinical trial.