Dr Gong on the Benefits and Limitations of PARP Inhibitor–Based Regimens in mCRPC

Jun Gong, MD, associate professor, medicine, medical oncologist, Gastrointestinal Disease Research Group, Pancreatic Cancer Research Group, Urologic Oncology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai, discusses the 

 of treatment with PARP inhibitor–based regimens for patients with metastatic castration-resistant prostate cancer (mCRPC), as well as common adverse effects (AEs) associated with these agents.

 State of Science Summit, Gong highlighted 3 key trials of novel PARP inhibitor combinations that have recently been approved in mCRPC. These agents represent the first targeted therapies specifically approved for this type of cancer, he reports, marking their approval as a significant advancement in the treatment space.

, which gained FDA approval for the same indication in August 2023; and 

talazoparib (Talzenna) plus enzalutamide (Xtandi)

, which was granted approval for patients with homologous recombination repair gene–mutated mCRPC in June 2023.

PARP inhibitor-based combinations are highly effective and provide a targeted therapeutic approach for patients with mCRPC, Gong continues. Prior clinical trials have shown improved outcomes with these combinations, Gong states. However, despite their efficacy, these combinations are not without their limitations, he notes.

One of the major concerns with PARP inhibitor–based therapies are treatment-related AEs, he reports. The most common and clinically relevant AE observed with these therapies is myelosuppression, which increases the risk of hematologic toxicities, Gong explains. More specifically, anemia poses a significant challenge for patients treated with a PARP inhibitor Gong states, adding that approximately 40% to 50% of patients will eventually require a blood transfusion. This is a substantial proportion of patients and underscores the importance of vigilant monitoring and proactive management, he emphasizes.

Timely interventions, such as dose adjustments or supportive care measures, are needed to mitigate the impact of anemia and other hematologic AEs in this patient population, Gong concludes.

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Jun Gong, MD, discusses the benefits and limitations of PARP inhibitor–based regimens in metastatic castration-resistant prostate cancer.

Dr Gong on the Importance of Molecular Profiling in mCRPC

Jun Gong, MD, associate professor, medicine, medical oncologist, Gastrointestinal Disease Research Group, Pancreatic Cancer Research Group, Urologic Oncology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai, discusses the importance of molecular profiling when determining optimal treatment approaches for patients with metastatic castration-resistant prostate cancer (mCRPC), as well as which PARP inhibitor–based regimens are indicated for patients with specific mutational profiles.

The emergence of targeted therapies in the mCRPC treatment paradigm underscores the necessity of next-generation sequencing and molecular profiling, especially as several PARP inhibitor–based combinations are indicated for patients with specific mutational profiles, Gong says. To identify candidates for these PARP inhibitor combinations, oncologists can order germline or genetic testing, both of which are recommended by the National Comprehensive Cancer Network guidelines for patients with metastatic prostate cancer, Gong notes. Somatic testing via tissue biopsies or liquid biopsies, such as circulating tumor DNA–based assays, can also be employed to detect DNA damage repair mutations, according to Gong.

Knowledge of patients’ treatment history is also crucial when determining the optimal treatment regimen, Gong explains. Currently, all PARP inhibitor–based combinations that are FDA approved for the treatment of patients with CRPC are indicated for the frontline metastatic setting. However, ongoing research is investigating the use of these regimens earlier in the disease course for patients with metastatic castration-sensitive prostate cancer, Gong adds. Identifying driver mutations at early stages of advanced prostate cancer through somatic or liquid-based testing is therefore crucial, Gong says.

Once mutations are confirmed, patients need to be stratified based on the type of DNA damage repair mutation they display, Gong emphasizes. For patients with 

-mutated mCRPC, all 3 FDA-approved PARP inhibitor–based combinations are applicable. However, the phase 3 TALAPRO-2 trial (NCT03395197) regimen should be considered for patients harboring other mutations, such as mutations in 

. The regimen consists of talazoparib (Talzenna) plus enzalutamide (Xtandi), and is indicated for a broader mCRPC patient population, Gong concludes.

Jun Gong, MD, discusses the importance of molecular profiling when determining optimal treatments for patients with mCRPC.

Dr Gong on the Frontline Use of PARP Inhibitors in mCRPC

Jun Gong, MD, associate professor, medicine, medical oncologist, Gastrointestinal Disease Research Group, Pancreatic Cancer Research Group, Urologic Oncology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai, discusses the variety of frontline PARP inhibitor–based treatment regimens that are FDA approved for patients with metastatic castration-resistant prostate cancer (mCRPC).

Three pivotal clinical trials led to the FDA approvals of 3 different PARP inhibitor–based combinations for the treatment of patients with treatment-naive mCRPC, Gong says. The phase 3 PROPEL trial (NCT03732820) evaluated the PARP inhibitor olaparib (Lynparza) in combination with the androgen receptor signaling inhibitor (ARSI) abiraterone acetate (Zytiga). The phase 3 TALAPRO-2 trial (NCT03395197) investigated the PARP inhibitor talazoparib (Talzenna) combined with the ARSI enzalutamide (Xtandi). The phase 3 MAGNITUDE trial (NCT03748641) examined the combination of the PARP inhibitor niraparib (Zejula) and abiraterone. All 3 trials demonstrated superior radiographic progression-free survival (rPFS) outcomes with the PARP inhibitor combinations vs their respective control arms. For instance, in TALAPRO-2, the median rPFS was not reached (NR; 95% CI, 27.5 months-NR) with talazoparib vs 21.9 months (95% CI, 16.6-25.1) with placebo. The median follow-up was 24.9 months (IQR, 21.9-30.2) for the talazoparib arm and 24.6 months (IQR, 14.4-30.2) for the arm of patients who received placebo plus enzalutamide.

The regimens from all 3 trials received FDA approval for use in the first-line mCRPC setting. However, the indications for these regimens have nuanced differences, Gong emphasizes. Olaparib plus abiraterone and prednisone or prednisolone 

 for the treatment of patients with deleterious or suspected deleterious 

-mutated mCRPC. Niraparib plus abiraterone 

 for this indication. Talazoparib plus enzalutamide 

 for use in patients with homologous recombination repair gene–mutated mCRPC. Whereas the PROPEL and MAGNITUDE regimens are limited to patients displaying 

 mutations, in contrast, the TALAPRO-2 regimen has a broader FDA label and can be used in a wider array of patients, Gong concludes.

Jun Gong, MD, discusses the variety of PARP inhibitor–based frontline treatment regimens that are FDA approved for patients with mCRPC.

Jun Gong, MD, discusses the significance of the phase 3 EMBARK study of enzalutamide in nonmetastatic castration-sensitive prostate cancer.

Dr Gong on the EMBARK Trial Investigating Enzalutamide in nmCSPC

Jun Gong, MD, medical director, Colorectal Cancer; associate professor, medicine; medical oncologist, Gastrointestinal Disease Research Group, Pancreatic Cancer Research Group, Urologic Oncology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Cancer, discusses the significance of the phase 3 EMBARK study (NCT02319837) investigating enzalutamide (Xtandi) in nonmetastatic castration-sensitive prostate cancer (nmCSPC).

the FDA approved enzalutamide for patients with nmCSPC

 and biochemical recurrence at high risk for metastasis. This regulatory approval was supported by 

The prospective trial enrolled 1,068 patients who had undergone prostatectomy with or without radiation therapy for localized disease. Notably, patients who were deemed at high risk of biochemical recurrence following primary therapy for localized prostate cancer were the main focus of the trial, Gong details. Biochemical recurrence was defined as a prostate-specific antigen doubling times of 9 months or less, Patients were assigned to receive either standard luteinizing hormone–releasing hormone (LHRH) therapy plus a placebo, LHRH therapy plus 160 mg of enzalutamide, or open-label enzalutamide monotherapy at 160 mg daily.

Results demonstrated that the combination of enzalutamide and ADT outperformed the LHRH placebo arm in terms of metastasis-free survival (MFS), with a hazard ratio (HR) of 0.42 (95% CI, 0.30-0.61; 

 < .001). Overall survival data are currently immature, but a trend in favor of enzalutamide over LHRH alone was observed. The enzalutamide monotherapy arm also showed superior MFS compared with the LHRH arm, with an HR for metastasis or death of 0.63 (95% CI, 0.46-0.87; 

These findings suggest that the use of ADT plus enzalutamide or enzalutamide alone confers a superior survival benefit in this population of patients with high-risk localized prostate cancer who experience biochemical recurrence, Gong emphasizes. Consequently, the utilization of enzalutamide in the prostate cancer community is expected to increase based on the pivotal results of the EMBARK study and the regimen's subsequent FDA approval, Gong concludes.

Jun Gong, MD, discusses the current treatment armamentarium for patients with metastatic hormone-sensitive prostate cancer.

Dr Gong on the Current Treatment Armamentarium in mHSPC

Jun Gong, MD, medical director, Colorectal Cancer; associate professor, medicine; medical oncologist, Gastrointestinal Disease Research Group, Pancreatic Cancer Research Group, Urologic Oncology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Cancer, discusses the current treatment armamentarium for patients with metastatic hormone-sensitive prostate cancer (mHSPC), highlighting the use of triplet therapeutic options.

mHSPC accounts for only a small percentage of newly diagnosed prostate cancer cases, as most patients present with localized disease, Gong begins. However, patient prognosis significantly worsens with metastatic disease, dropping from an approximately 90% 5-year overall survival (OS) rate with localized disease to an OS rate of less than 40%, he states. mHSPC management historically involved androgen deprivation therapy (ADT) alone, but over the past decade, there has been a shift toward the intensification of ADT through the incorporation of additional agents, Gong explains.

These additional agents include docetaxel, androgen receptor signaling inhibitors (ARSIs) such as abiraterone acetate (Zytiga), and enzalutamide (Xtandi), he expands. Furthermore, recent phase 3 trials, such as PEACE1 (NCT01957436) and ARASENS (NCT02799602), have investigated triplet therapy—ADT plus docetaxel plus an ARSI—which has become a new standard of care (SOC), particularly for high-volume de novo mHSPC, despite the increased adverse effects, he adds. However, 

questions remain about the optimal use of these triplet therapies

. For example, it is still unknown how to best identify which patients may benefit from treatment intensification with a triplet therapeutic approach in mHSPC.

The PEACE1 trial was a multicenter study comparing the clinical benefit of SOC ADT with or without docetaxel alone vs SOC plus local radiotherapy vs SOC plus abiraterone vs SOC plus radiotherapy and abiraterone in mHSPC. Conversely, the purpose of the ARASENS study was to assess the efficacy and safety of darolutamide (Nubeqa) in combination with standard ADT and docetaxel in this patient population. This intensified treatment approach has shown superior outcomes compared with traditional chemotherapy-based doublet therapy, especially in specific subsets of patients, Gong concludes.

Dr. Gong on Addressing Unmet Needs Through Ongoing Research in Prostate Cancer  

Jun Gong, MD, medical director, Colorectal Cancer; associate professor, medicine; medical oncologist, Gastrointestinal Disease Research Group, Pancreatic Cancer Research Group, Urologic Oncology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Cancer, discusses efforts to address unmet needs in metastatic hormone-sensitive prostate cancer (mHSPC) through ongoing biomarker research and real-world analysis of triplet therapy integration in clinical practice.

The decision-making process for determining an appropriate therapy regimen for patients with mHSPC is evolving, particularly in terms of triplet vs doublet therapeutic approaches, Gong begins. Whether to stratify patient benefit according to volume of disease, or de novo vs metastatic disease is an ongoing question in this space, he adds, stating that accordingly, identifying biomarkers to guide treatment selection in this setting is crucial.

One such biomarker of interest is SPOP, which has emerged as a potential predictor of treatment response in de novo mHSPC, Gong introduces. Early data from studies conducted at the Huntsman Cancer Center showed that the presence of 

mutations were significantly associated with improved outcomes with androgen receptor signaling inhibitor (ARSI)–based therapies vs wild-type SPOP, Gong states. This efficacy signal was not observed with docetaxel-based therapy in patients with 

 mutations, he notes. Such findings indicates that SPOP status could help identify patients who would benefit from ARSI-based treatment strategies, Gong explains.

Despite the emerging evidence supporting the intensification of androgen deprivation therapy (ADT), there is a notable gap between evidence-based recommendations and their implementation in real-world practice, Gong continues. Real-world analyses have shown that a significant portion of patients with mHSPC are still receiving monotherapy with ADT compared with a doublet or intensified therapy regimens, he reports. This highlights the need for increased awareness and education within the medical community to ensure that all eligible patients have access to and benefit from the latest treatment strategies that can prolong overall survival and improve outcomes, Gong explains.

Efforts to disseminate knowledge and encourage the adoption of treatment intensification strategies are therefore essential to address this unmet need and optimize patient care in mHSPC, Gong says. Bridging the gap between evidence-based recommendations and clinical practice will ensure that patients receive the most appropriate and effective therapies based on their individual biomarker profiles, he concludes.

Jun Gong, MD, discusses efforts to address unmet needs in metastatic hormone-sensitive prostate cancer. 

Jun Gong, MD, fellow, City of Hope, discusses adverse events (AEs) associated with TKI/VEGF-directed therapy for patients with metastatic renal cell carcinoma (RCC).

In a study evaluating latency of potential treatment-related AEs, toxicities reported after the first drug claim up until the last drug claim were tracked. With a population of a little over 1000 and a median age of 62, the most common AEs were fatigue, hypertension, diarrhea and thyroid dysfunction. The median time of onset reported by patients was beyond 100 days.

Some side effects are more easily reportable, such as nausea or vomiting, but something that is determined by a blood test might not show symptoms. The number of patients who don’t report symptoms or decide to wait them out was much higher than researchers anticipated.

The next steps, says Gong, is telling the scientific community that there needs to be more investigation into side effects, as many phase II and III RCC studies do not report time of onset toxicities.

Jun Gong, MD

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