<p>Targeted treatments for prostate cancer are improving patient care and outcomes. Emerging data on various targeted therapies for prostate cancer were presented at the recent <strong>ESMO Congress 2024</strong>.</p> <p><strong> </strong><strong> </strong><strong> </strong></p> <p><em>Following these proceedings, featured expert Andrew J. Armstrong, MD, MSc, was interviewed by</em> Conference Reporter<em> Associate Editor-in-Chief Christopher Ontiveros, PhD. Dr Armstrong’s clinical perspectives on these findings are presented here</em><em>.</em></p>

Targeted therapy refers to treatments that act on cancer cells with a known important target inside or on their surface. There are several targeted therapies available for prostate cancer. PARP inhibitors are oral targeted therapies that block the PARP enzyme and include olaparib, niraparib, talazoparib, and rucaparib. They tend to work in patients with a germline or somatic (tumor-specific) mutation or deletion in 1 or more DNA repair genes, such as BRCA2. PARP inhibitors have certainly been one of the big breakthroughs in the past couple of years and may be used as monotherapy and in combination with ARPIs, which are also targeted therapies and include darolutamide, enzalutamide, apalutamide, and abiraterone. The AR is the most important target in prostate cancer and is present and overexpressed or amplified in most patients with metastatic castration-resistant prostate cancer (mCRPC). Thus, most people benefit from ARPIs, and, in fact, these agents work even better when used prior to castration resistance.

 

Some studies presented at the ESMO Congress 2024 investigated the roles of these AR-targeted therapies. One such study was the ARANOTE trial, which evaluated the efficacy and safety of darolutamide plus ADT in patients with metastatic hormone-sensitive prostate cancer (mHSPC; abstract LBA68). Similar to the results that have been reported with the other ARPI/ADT studies over the past 5 or more years, the ARANOTE trial investigators found that the combination of darolutamide plus ADT significantly delayed progression-free survival (PFS) vs placebo plus ADT by 46%. The nice thing about darolutamide is that it lacks the need for steroids and has a very clean toxicity profile without some of the toxicities that are seen in some patients with other ARPIs, such as cognitive dysfunction, fractures, and fall risk. However, hot flashes, fatigue, and cardiovascular, bone, and muscle health are fairly universally impacted by hormonal therapy, emphasizing the need for good survivorship care. If patients have access to and can afford this agent, darolutamide could become an approved standard of care in many parts of the world, which would make darolutamide the fourth ARPI, along with abiraterone, enzalutamide, and apalutamide, that is effective as doublet therapy with ADT. While overall survival (OS) has not improved in ARANOTE, the data are quite immature, and darolutamide had a survival benefit in this setting in the ARASENS study.

 

Radioligand therapy (RLT) is also available as a targeted prostate cancer treatment. The ligands are small-molecule binders or antibodies that target specific molecules on cancer cells, allowing you to precisely deliver the radioactive warhead to them. Prostate-specific membrane antigen (PSMA) lutetium is one such RLT, as PSMA is expressed on the cell surface of most prostate cancer cells, although it is not prostate specific given its normal expression in the salivary tissues, lacrimal glands, kidneys, and bowel.

 

Researchers at the ESMO Congress 2024 presented new data from the phase 3 SPLASH trial of ¹⁷⁷Lu-PNT2002 RLT demonstrating a modest but significant improvement in radiographic PFS (rPFS) in patients with PSMA positron emission tomography–positive mCRPC post ARPI therapy as compared with a second ARPI, improving rPFS by approximately 3 months using a less intensive dosing regimen of once every 8 weeks for up to 4 cycles (abstract LBA65). OS was not improved, likely due to high rates of crossover. It will be interesting to see if the US Food and Drug Administration (FDA) approves this agent, given its modest efficacy in this setting without a survival benefit and given alternatives such as ¹⁷⁷Lu-PSMA-617, based on the results of the now-published phase 3 PSMAfore trial. This study demonstrated a 6-month rPFS benefit in a similar population using a schedule of once every 6 weeks for 6 cycles involving more radiation therapy and dose intensity.

 

This was a big comeback year for radium, in particular, at this year’s ESMO Congress, with the PEACE-3 trial demonstrating that the addition of radium-223, which is our only FDA-approved alpha emitter, to first-line enzalutamide therapy for bone poly-mCRPC significantly improved rPFS and OS vs enzalutamide monotherapy (abstract LBA1). The critical message from PEACE-3 was the requirement for the regular use of bone health agents (ie, zoledronic acid or denosumab), which lowers the fracture rate for this new doublet therapy (radium-223 plus enzalutamide) from approximately 30% to 45% to approximately 5% to 10%. The application of this trial in current practice is unclear, however, given that most patients receive treatment with ADT and ARPI in the mHSPC setting.

 

Over the past 2 years, we have seen major improvements in RLTs and the beta emitters. ¹⁷⁷Lu-PSMA-617 was FDA approved 2 years ago and is certainly a very popular therapy. It is positioned to move earlier into the prechemotherapy setting and possibly into the hormone-sensitive setting. Several other RLTs are in development to target molecules such as DLL3, GPC3, STEAP1, TROP2, CD64, CEACAM5, and bombesin receptors.

 

It is important to note that the words “targeted therapy” do not always imply that the drug is going to be well tolerated. Some of these agents are fairly “dirty” drugs, meaning that they have too many targets that can cause off-target side effects. This was demonstrated in the phase 3 CONTACT-02 study, with updated results presented at the ESMO Congress 2024 (abstract LBA67). The study tested the oral-targeted therapy cabozantinib in combination with the immunotherapy atezolizumab vs a second ARPI in patients with mCRPC. The study failed to improve OS, although it did significantly delay PFS and therefore met one of its primary end points. While there was activity, the low bar set by a second ARPI in this setting, particularly in patients with visceral/liver metastases, is not acceptable, and I think that such patients really should be treated with docetaxel. The magnitude of the results was probably not worth the added toxicities associated with the cabozantinib-plus-atezolizumab combination. When you have a drug that does not improve survival and adds side effects such as diarrhea, hand-foot syndrome, immune toxicities, or hypertension, we really expect to see greater benefits than just a 2- to 3-month delay in PFS without seeing patients live longer or better. I do not expect this regimen to become FDA approved for use.