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"This is quite reassuring to show that there's no statistically significant influence of BMI in actual complications," says Muhammed A. Moukhtar Hammad, MBBCh.

Does BMI affect inflatable penile prosthesis surgery?

The FDA has accepted a Biologics License Application (BLA) seeking approval of nivolumab (Opdivo) co-formulated with Halozyme’s proprietary recombinant human hyaluronidase (rHuPH20), or subcutaneous nivolumab, for the treatment of patients with all previously approved solid tumor indications for nivolumab as a monotherapy, monotherapy maintenance following completion of combination therapy with nivolumab plus ipilimumab (Yervoy), or in combination with chemotherapy or cabozantinib (Cabometyx).

Nivolumab is currently approved under several indications, including in combination with ipilimumab for the first-line treatment of patients with intermediate- or poor-risk advanced renal cell carcinoma (RCC), in combination with cabozantinib for the first-line treatment of patients with advanced RCC, for the treatment of patients with advanced RCC who have received prior anti-angiogenic therapy, and in combination with cisplatin and gemcitabine for the first-line treatment of patients with unresectable or metastatic urothelial carcinoma.

The FDA is set to have a decision regarding the subcutaneous nivolumab formulation on or by December 29, 2024.

 According to a news release from Bristol Myers Squibb,

 approval of the formulation would make it the first and only subcutaneously administered PD-1 inhibitor.

“We believe subcutaneous nivolumab has the potential to make a significant difference in the lives of patients, which is reinforced by the FDA’s acceptance of our application,” said Gina Fusaro, PhD, vice president, global program lead, Bristol Myers Squibb, in the news release.

 “Opdivo is a foundational PD-1 inhibitor approved for many different types of cancer, and our continued investment in research that puts patients first remains a priority. If approved by the FDA, the subcutaneous administration of nivolumab would provide patients and their physicians with a new option that delivers the same well-known benefits as IV Opdivo but with the improved convenience of an injection administered in 3 to 5 minutes rather than a 30-to-60-minute infusion.”

The BLA submission is supported by findings from the phase 3 CheckMate-67T trial (NCT04810078), in which subcutaneous nivolumab met the study’s co-primary end points by demonstrating noninferiority to intravenous (IV) nivolumab regarding time average nivolumab serum concentration over 28 days (C

; geometric mean ratio [GMR}, 2.098; 90% CI, 2.001-2.200) and minimum serum concentration at a steady state (C

Data from the study, which were presented at the 2024 American Society of Clinical Oncology Genitourinary Cancers Symposium in San Francisco, California,

 also showed that subcutaneous nivolumab demonstrated noninferiority to IV nivolumab in the key powered secondary end point of objective response rate (ORR). Specifically, the subcutaneous arm demonstrated an ORR of 24.2% (95% CI, 19.0-30.0) per blinded independent central review (BICR), compared with 18.2% (95% CI, 13.6-23.6) in the IV arm.

The safety profile for subcutaneous nivolumab was consistent with that of the IV formulation. Among patients who received the subcutaneous formulation, 8.1% experienced injection-site reactions, with all being low-grade and transient. Deaths due to study drug toxicity occurred in 3 patients in the subcutaneous arm and 1 patient in the IV arm. Most deaths that occurred during the study were due to disease progression.

In total, the phase 3, open-label CheckMate-67T trial enrolled 495 patients with advanced or metastatic ccRCC who had received prior systemic therapy. Patients were randomly assigned 1:1 to receive 1200 mg subcutaneous nivolumab plus rHuPH20 every 4 weeks (n = 248) or to 3 mg/kg IV nivolumab every 2 weeks (n = 247) for up to 2 years of treatment or until disease progression, unacceptable toxicity, withdrawal, or death.

The co-primary pharmacokinetic end points for noninferiority testing were C

 of subcutaneous nivolumab vs IV nivolumab. The key secondary end point was ORR per BICR.

Final completion of the CheckMate-67T study is expected in January 2026.

1. U.S. Food and Drug Administration accepts Bristol Myers Squibb’s application for subcutaneous nivolumab (nivolumab and hyaluronidase). News release. Bristol Myers Squibb. May 6, 2024. Accessed May 7, 2024. https://news.bms.com/news/corporate-financial/2024/U.S.-Food-and-Drug-Administration-Accepts-Bristol-Myers-Squibbs-Application-for-Subcutaneous-Nivolumab-nivolumab-and-hyaluronidase/default.aspx

2. Bristol Myers Squibb announces updated action date by the U.S. Food and Drug Administration for subcutaneous nivolumab (nivolumab and hyaluronidase). News release. Published online and accessed May 21, 2024. https://investors.bms.com/iframes/press-releases/press-release-details/2024/Bristol-Myers-Squibb-Announces-Updated-Action-Date-by-the-U.S.-Food-and-Drug-Administration-for-Subcutaneous-Nivolumab-nivolumab-and-hyaluronidase/default.aspx

3. George S, Bourlon TB, Chacon MR, et al. Subcutaneous nivolumab (NIVO SC) vs intravenous nivolumab (NIVO IV) in patients with previously treated advanced or metastatic clear cell renal cell carcinoma (ccRCC): Pharmacokinetics (PK), efficacy, and safety results from CheckMate 67T. 

4. A study of subcutaneous nivolumab versus intravenous nivolumab in participants with previously treated clear cell renal cell carcinoma that is advanced or has spread (CheckMate-67T). ClinicalTrials.gov. Last updated March 1, 2024. Accessed May 7, 2024. https://clinicaltrials.gov/study/NCT04810078

The FDA is set to have a decision regarding the subcutaneous nivolumab formulation on or by December 29, 2024. 

News

FDA accepts BLA for subcutaneous nivolumab in solid tumors

Key Trials on PARP Inhibitor Combinations in Metastatic Prostate Cancer: Efficacy and Future Considerations

Video Content above is prompted by the following:

The TALAPRO-2 study authors noted that the use of androgen receptor (AR)–targeted therapy in clinical practice has increased considerably in recent years. How might prior use of AR-targeted therapy affect the effectiveness of this combination?

What are the main safety concerns with use of talazoparib and other PARP inhibitors (eg, anemia, neutropenia, thrombocytopenia)? Would these make you more hesitant to use PARP inhibitors compared with another option?

How do you expect the results found in the TALAPRO-2 trial population to compare to that in the ZZ-First trial (NCT04332744) population (metastatic hormone-naive prostate cancer)?

What future studies are needed to clarify the optimal approaches for different populations of people with metastatic prostate cancer?

The TALAPRO-2 study highlights the increased use of androgen receptor (AR)-targeted therapy in clinical practice and examines its impact on the efficacy of combination treatments. Safety concerns with talazoparib and other PARP inhibitors, such as anemia, neutropenia, and thrombocytopenia, are discussed, raising questions about their use compared to other options. The study also considers how results might differ from the ZZ-First trial, which focuses on metastatic hormone-naive prostate cancer. Future research is needed to determine optimal treatment strategies for various metastatic prostate cancer populations.

Panelists discuss how the increased use of androgen receptor–targeted therapy in clinical practice may impact the effectiveness of PARP inhibitor combinations like talazoparib in the TALAPRO-2 study, while also addressing safety concerns, potential differences in trial populations, and the need for future studies to optimize treatment approaches for various metastatic prostate cancer patient subgroups.

Investigator Perspectives

Video Series

PARP Inhibitors in Metastatic Prostate Cancer: Efficacy, Trials, and Combination Therapies

Discuss efficacy and safety findings from monotherapy trials PARP inhibitors in metastatic prostate cancer harboring homologous recombination repair gene alterations.

PARP inhibitors, particularly olaparib, have shown promise in treating metastatic prostate cancer with homologous recombination repair (HRR) gene alterations. The PROfound trial demonstrated olaparib's efficacy, significantly improving radiographic progression-free survival and overall survival compared to standard treatments. Safety profiles were consistent with known PARP inhibitor effects, with manageable adverse events. These findings underscore the potential of PARP inhibitors as a targeted therapy for patients with HRR gene alterations, offering a personalized treatment approach and highlighting the importance of genetic testing in guiding therapeutic decisions.

Panelists discuss how the PROfound trial (NCT02987543) demonstrated the efficacy and safety of olaparib monotherapy in metastatic prostate cancer patients with homologous recombination repair gene alterations, highlighting its potential as a targeted treatment option and its impact on the landscape of precision medicine in prostate cancer management.

Genetic Testing in Metastatic Prostate Cancer: Key Insights on Germline and Somatic Mutations

Discuss efficacy and safety findings from monotherapy trials of PARP inhibitors in metastatic prostate cancer harboring homologous recombination repair (gene alterations. 

TALAPRO-1 trial (talazoparib), NCT03148795

Monotherapy trials of PARP inhibitors, specifically talazoparib and rucaparib, have shown promising efficacy in treating metastatic prostate cancer with homologous recombination repair gene alterations. The TALAPRO-1 trial demonstrated talazoparib's potential in improving progression-free survival and overall response rates. Similarly, the TRITON3 trial highlighted rucaparib's effectiveness in prolonging progression-free survival compared to standard treatments. Both trials underscored the importance of genetic profiling in selecting patients who would benefit most from PARP inhibitors. Safety profiles were consistent with known side effects, emphasizing the need for careful patient monitoring.

Panelists discuss how PARP inhibitor monotherapy trials like TALAPRO-1 (talazoparib) and TRITON-3 (rucaparib) have demonstrated efficacy and safety in treating metastatic prostate cancer patients with homologous recombination repair gene alterations, providing important insights into targeted therapy options for this specific patient population.

Radium-223 and Enzalutamide: Game-Changing PEACE III Phase 3 Data in mCRPC

Discuss the findings from the PEACE III trial, which compared enzalutamide with enzalutamide plus radium-223 in patients with previously untreated castration-resistant prostate cancer that has metastasized to bone.

Giving bone-protective agents (BPAs) to patients receiving radium-223 in PEACE III nearly eliminated risk for skeletal fracture (fracture incidence was 33% without BPAs and 3% with BPAs) (Tombal et al [2019])

This is proving that enzalutamide doublet shouldn’t be used anymore. Radium-223 triplet on top of ARI doublet (in metastatic castration-resistant prostate cancer) is superior combination. Unless there’s a big safety signal, this study will now prove that radium-223 triplet beats enzalutamide doublet.

In which patients would you consider using an enzalutamide–radium-223 combination? (Shariftabrizi et al [2023])

What would be absolute or relative contraindications for radium-223 use?

What bone support/monitoring strategies (eg, bone-protective agent use, bone density scans) are needed to improve safety of radium-223 in clinical practice? (Tombal et al [2019])

What strategies would you recommend for increasing utilization for bone health in general for all metastatic patients?

The PEACE III trial evaluated the efficacy of enzalutamide alone versus enzalutamide combined with radium-223 in patients with bone-metastasized, castration-resistant prostate cancer. The trial demonstrated that the addition of bone-protective agents (BPAs) significantly reduced skeletal fracture risk from 33% to 3%. The findings suggest that the radium-223 triplet regimen is superior to the enzalutamide doublet, barring any major safety concerns. The study emphasizes the importance of BPAs and bone health monitoring in improving the safety and efficacy of radium-223 in clinical practice.

Panelists discuss how the PEACE III trial findings demonstrate the superiority of combining radium-223 with enzalutamide in treating metastatic castration-resistant prostate cancer, highlighting improved efficacy, the critical importance of bone-protective agents in reducing fracture risk, and the potential for this triplet  therapy to become the new standard of care over enzalutamide alone.

The Evolving Role of Radium-223 in mCRPC and the Impact of Combination Therapies

What are the challenges, historically, that the PEACE III study addresses?

Discuss reasons for the relatively poor uptake of radium-223 (Xofigo) in the clinic.

Radium alone doesn’t control prostate-specific androgen (PSA), nor does docetaxel. PSA control is addressed by androgen receptor inhibitor (ARI).

Layered radium-223 and enzalutamide plus ARI will control PSA, so radium-223 can be administered without being questioned or second-guessed.

Similar to the ARASENS trial, maintain relationship and management and share care with med oncology for docetaxel.

Discuss the rationale for combining radium-223 with androgen receptor–targeted therapy (enzalutamide). (Sartor et al [2018]; Shore et al [2020])

Allows for 2 distinct mechanisms of action.

The PEACE III study addresses historical challenges in prostate cancer treatment by exploring the combination of radium-223 with androgen receptor-targeted therapies like enzalutamide. This approach aims to improve PSA control, which radium-223 and docetaxel alone do not achieve. The study seeks to enhance the clinical uptake of radium-223 by demonstrating its efficacy when combined with androgen receptor inhibitors. This combination leverages two distinct mechanisms of action, potentially improving patient outcomes. Collaboration with medical oncology for docetaxel management is emphasized, similar to the ARASENS trial.

Panelists discuss how combining radium-223 with androgen receptor–targeted therapy like enzalutamide addresses historical challenges in treating metastatic castration-resistant prostate cancer, including poor radium-223 uptake, prostate-specific androgen–level control issues, and the need for multimodal treatment approaches.

Muhammed A. Moukhtar Hammad, MBBCh

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