oshi Alumkal, MD, Wicha Family Professor of Oncology, professor, Department of Internal Medicine, section head, Prostate and Genitourinary Medical Oncology, associate division chief, Basic Research, Division of Hematology-Oncology, member, the University of Michigan Rogel Cancer Center, director, Epigenetic Therapy, Michigan Center for Translational Pathology, discusses treatment options for patients with metastatic castrate-resistant prostate cancer (mCRPC) harboring homologous recombination deficient (HRD)alterations, including PARP inhibitors.

Genomic profiling studies have demonstrated the prevalence of homologous recombination repair (HRR) defects in mCRPC, Alumkal begins. Unlike hormone-naive prostate cancer, where such defects are less common, patients with mCRPC have a higher incidence of these genomic abnormalities, Alumkal states. This finding suggests two potential scenarios, he says: HRR mutations emerge as an adaptive mechanism in response to therapy or tumors prone to metastasizing or developing castration resistance inherently harbor HRR defects.

Emerging data indicate that approximately 20% of patients with mCRPC may have HRD tumors, Alumkal continues. Accordingly, several clinical investigations have been conducted to assess the efficacy of PARP inhibitors in this population. Tumor cells exhibiting HRR defects are unable to repair DNA via the normal double-stranded DNA repair process, Alumkal details. Consequently, these cells resort to utilizing PARP proteins for single-strand DNA repair. This disrupts the cell's single-stranded DNA repair mechanism, preventing effective DNA damage repair and often culminating in cell death, Alumkal explains.

Clinical trials focused on patients with mCRPC and HRR defects have consistently demonstrated that PARP inhibitors provide superior benefit compared with conventional treatment options, which include other androgen receptor signaling inhibitors (ARSIs) or chemotherapy agents, Alumkal reports. However, the therapeutic landscape has expanded to include radiopharmaceuticals like lutetium Lu 177 vipivotide tetraxetan (Pluvicto; formerly 177Lu-PSMA-617) and Radium-223 (Xofigo), he adds. These new agents provide oncologists with additional tools to manage this challenging patient population.

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Joshi Alumkal, MD, discusses treatment options for patients with metastatic castrate-resistant prostate cancer harboring homologous recombination deficient alterations, including PARP inhibitors.

Dr Alumkal on Standard Treatment Options For Patients With HRD-Altered mCRPC

Joshi Alumkal, MD, Wicha Family Professor of Oncology, professor, Department of Internal Medicine, section head, Prostate and Genitourinary Medical Oncology, associate division chief, Basic Research, Division of Hematology-Oncology, member, the University of Michigan Rogel Cancer Center, director, Epigenetic Therapy, Michigan Center for Translational Pathology, discusses the use of triplet therapy in prostate cancer.

The optimal use of the triplet combination of androgen deprivation therapy (ADT), docetaxel (Taxotere), and an androgen receptor signaling inhibitor is unknown, Alumkal begins. The phase 3 PEACE-1 trial (NCT01957436), which investigated ADT, docetaxel, and abiraterone acetate (Zytiga) vs ADT, docetaxel, and placebo, showed an overall survival (OS) benefit with the addition of abiraterone to ADT and docetaxel in patients with metastatic hormone-naïve prostate cancer, Alumkal explains. These findings were similar to those of the phase 3 ARASENS trial (NCT02799602), he adds.

However, neither of these trials featured a control arm where patients just received ADT and an androgen receptor signaling inhibitor, Alumkal says. The ARASENS trial did not have an arm that received ADT and darolutamide, and the PEACE-1 trial did not have an arm that received ADT plus abiraterone, Alumkal expands. Therefore, it remains unknown whether ADT plus an androgen receptor signaling inhibitor would be sufficient for many patients, or whether the addition of docetaxel is necessary, he explains.

Trials investigating the efficacy of ADT plus an androgen receptor signaling inhibitor with or without docetaxel have yet to be conducted, leaving an unmet need for patients with prostate cancer, he continues. Since many patients are hesitant to start chemotherapy with docetaxel, collecting level 1 evidence to show these patients the OS advantages of adding an androgen receptor signaling inhibitor to ADT is important, Alumkal emphasizes. However, for patients who want their prostate cancer treatment to be as aggressive as possible, data indicate that the triplet combination is more effective than the doublet combination of chemotherapy plus ADT, he notes. Younger patients who are more symptomatic or have more advanced prostate cancer tend to be most interested in treating their disease with an ADT, chemotherapy, and an androgen receptor signaling inhibitor, he concludes.

Joshi Alumkal, MD, discusses the use of triplet therapy in prostate cancer.


Dr Alumkal on Triplet Therapy in Prostate Cancer

Joshi Alumkal, MD, Wicha Family professor of oncology, professor, Department of Internal Medicine, section head, Prostate and Genitourinary Medical Oncology, associate division chief for Basic Research, Division of Hematology-Oncology, member, the University of Michigan Rogel Cancer Center, director, Epigenetic Therapy, Michigan Center for Translational Pathology, discusses the effects of the phase 3 ARESENS trial (NCT02799602) on the treatment of metastatic hormone-sensitive prostate cancer (mHSPC).

For the past several years, oncologists have been treating patients with mHSPC with androgen receptor signaling inhibitors in addition to androgen deprivation therapy (ADT), Alumkal begins. An alternative treatment approach for these patients is ADT plus docetaxel, he notes. However, in the past, oncologists did not know the importance of the androgen receptor signaling inhibitor darolutamide (Nubeqa), or the value of adding an androgen receptor signaling inhibitor to chemotherapy, Alumkal explains.

In light of these new discoveries in the prostate cancer treatment arena, investigators launched the phase 3 ARESENS trial, he expands. This was a randomized phase 3 clinical trial comparing ADT plus docetaxel and placebo vs ADT plus docetaxel and darolutamide in patients with mHSPC. Notably, this double-blind, placebo-controlled, multicenter trial showed an improvement in survival for patients treated with triplet combination therapy consisting of ADT, docetaxel, and darolutamide vs those who received placebo plus ADT and docetaxel, Alumkal says.

These data strongly indicate that if an oncologist chooses to treat a patient with mHSPC with ADT and docetaxel, it's advantageous to add darolutamide to that combination vs omitting the drug, he continues. Based upon these encouraging results, 

the FDA has approved the use of darolutamide in combination with docetaxel

 in adult patients with mHSPC, Alumkal emphasizes. Darolutamide plus docetaxel and ADT is an active regimen that oncologists should consider in patients who present with metastatic disease, he concludes.

Joshi Alumkal, MD, discusses the effects of the phase 3 ARESENS trial on the treatment of metastatic hormone-sensitive prostate cancer.


Joshi Alumkal, MD

Articles

Dr Alumkal on Standard Treatment Options For Patients With HRD-Altered mCRPC

Dr Alumkal on Triplet Therapy in Prostate Cancer

Dr Alumkal on the Effects of the ARESENS Trial on the Treatment of mHSPC