Abstract
Simple SummaryProstate cancer still represents an important health problem in men, considering its high frequency. Over the last decade, novel treatment options have emerged, leading to notable clinical benefits. These recent scientific acquisitions are creating the basis to widen the treatment scenario of this tumor, evolving from targeting the androgen receptor axis or the traditional chemotherapy approach.In recent years, the advances in the knowledge on the molecular characteristics of prostate cancer is allowing to explore novel treatment scenarios. Furthermore, technological discoveries are widening diagnostic and treatment weapons at the clinician disposal. Among these, great relevance is being gained by PARP inhibitors and radiometabolic approaches. The result is that DNA repair genes need to be altered in a high percentage of patients with metastatic prostate cancer, making these patients optimal candidates for PARP inhibitors. These compounds have already been proved to be active in pretreated patients and are currently being investigated in other settings. Radiometabolic approaches combine specific prostate cancer cell ligands to radioactive particles, thus allowing to deliver cytotoxic radiations in cancer cells. Among these, radium-223 and lutetium-177 have shown promising activity in metastatic pretreated prostate cancer patients and further studies are ongoing to expand the applications of this therapeutic approach. In addition, nuclear medicine techniques also have an important diagnostic role in prostate cancer. Herein, we report the state of the art on the knowledge on PARP inhibitors and radiometabolic approaches in advanced prostate cancer and present ongoing clinical trials that will hopefully expand these two treatment fields.
Highlights
Excluding skin cancer, prostate cancer (PCa) is still the most common tumor diagnosed in men
Regarding the interesting results of the recent phase II TheraP trial, that compared Cabazitaxel versus Lu-PSMA-617, a beta emitter that binds a prostate-specific membrane antigen (PSMA), several potential alternatives are yet to arise [11]. Another important therapeutic field being investigated in metastatic CRPC (mCRPC) is based on the percentage of patients, estimated to be about a 23%, with deleterious alterations in genes involved in homologous recombination repair (HRR), mainly BRCA1, BRCA2, and ATM [12]
We reported studies supporting the rationale and clinical trials to present the current knowledge on these two approaches
Summary
Prostate cancer (PCa) is still the most common tumor diagnosed in men. Regarding the interesting results of the recent phase II TheraP trial, that compared Cabazitaxel versus Lu-PSMA-617, a beta emitter that binds a prostate-specific membrane antigen (PSMA), several potential alternatives are yet to arise [11] Another important therapeutic field being investigated in mCRPC is based on the percentage of patients, estimated to be about a 23%, with deleterious alterations in genes involved in homologous recombination repair (HRR), mainly BRCA1, BRCA2, and ATM [12]. The “synthetic lethality” induced by exogen blockade of base excision repair (BER) machinery, used by tumor cells to escape the HRR defect; the PARPi binds and “traps” PARP-1 enzyme on the chromatin, creating a damage necessitating HRR for its removal, and the enhancement of non-homologous end joining, which may elicit a tumoricidal effect [13] Referring to this biological rationale, several studies investigate olaparib, an orally bioavailable PARP inhibitor approved for advanced ovarian and breast cancer, highlighting its antitumor activity in mCRPC in patients with specific genomic damage [14,15]. A study published in 2017 suggested that the potential use of PARPi combined with ADT could be effective before the development of CRPC, in advanced or high-risk patients [33]
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