Advances in Cancer Biology Benefit Broad GU Treatments

Targeted Therapies in Oncology, February 1, 2021, Volume 10, Issue 2
Pages: 52

The treatment landscape of genitourinary malignancies has seen tremendous growth in the last decade with advancements in prostate, bladder, and urothelial cancers.

The treatment landscape of genitourinary (GU) malignancies has seen tremendous growth in the last decade with advancements in prostate, bladder, and urothelial cancers. Synthesizing and incorporating these developments into patient care and the clinical workflow is the primary objective of the New York GU™14th Annual Interdisciplinary Prostate Cancer Congress®, hosted by Physicians’ Education Resource®, LLC (PER®), which will be held virtually March 12-13, 2021.

In an interview with Targeted Therapies in Oncology, cochair Leonard G. Gomella, MD, the Bernard W. Godwin, Jr. Professor of Prostate Cancer and chair of Department of Urology at the Kimmel Cancer Center Network, Jefferson University Hospitals in Philadelphia, Pennsylvania, provided his insights on the latest developments in the genitourinary setting.

Prostate Cancer

Prostate cancer, in particular, has seen a broadening of therapies and classifications. The term “advanced prostate cancer” is no longer reserved for metastatic castration resistant prostate cancer (mCRPC) but includes metastatic hormone sensitive prostate cancer (mHSPC) and even localized disease characterized by high-risk features.

These changes coincide with a greater understanding of the underlying genomic complexity of prostate cancer and with the implementation of improved imaging techniques that identify patients who had previously occult metastatic disease.

Gomella highlighted the greater use of circulating tumor DNA (ctDNA) to determine genetic susceptibility as a significant advance in prostate cancer. Genomic profiling assays that use ctDNA have been developed and are used routinely in the clinic, and ctDNA’s use has grown because of commercially available tests.

In addition, its practical benefit was boosted with the approval of the PARP inhibitor olaparib (Lynparza). In May 2020, the FDA approved the agent for adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair gene-mutated mCRPC who progressed on prior treatment with enzalutamide (Xtandi) or abiraterone acetate (Zytiga).1 A few days later, rucaparib(Rubraca) gained approval for patients with deleterious BRCA mutation (germline or somatic)-associated mCRPC. Alterations in homologous recombination repair (HRR) genes, which have been associated with response to PARP inhibitors, can be tracked using ctDNA.

Two companion diagnostic tests were simultaneously approved with olaparib: the FoundationOne CDx test (Foundation Medicine) to select patients with mCRPC who carry HRR gene alterations and the BRACAnalysis CDx test (Myriad Genetics) for selection of patients with mCRPC who carry the germline BRCA1/2 alterations.

PARP inhibitors interfere with the ability of DNA in a malignant cell with a repair defect to repair itself so that it does not continue to grow. This makes the identification of these repair pathway genes important for potentially screening not only for prostate cancer, but for other at-risk cancers, such as breast cancer in males, melanoma, or pancreatic cancer.

“Identification of these genetic alterations is giving us another alternative pathway to treat these men who may unfortunately, ultimately develop medical metastatic castration-resistant prostate cancer,” Gomella said.

On the hormonal front, Gomella noted the approval of the oral agent relugolix (Relumina), a first-in-class gonadotropin-releasing hormone antagonist (GnRH receptor antagonist) as a treatment for men with advanced prostate cancer.

The approval comes based on findings from the phase 3 HERO clinical trial (NCT03085095), which demonstrated the superiority of relugolix over standard-of-care leuprolide acetate (Lupron) and was presented during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Meeting.2

The agent has the potential to reduce clinic visits, thereby reducing patient exposure during the coronavirus disease 2019 pandemic.

Technologies to enable more precise detection of prostate cancer are also a promising advancement, Gomella said, referring to the approval of Gallium 68 PSMA-11 (Ga 68 PSMA-11), the first drug for positron emission tomography imaging of prostate-specific membrane antigen (PSMA) positive lesions in men with prostate cancer.

According to the FDA approval, Ga 68 PSMA-11 is indicated for patients with suspected prostate cancer metastasis who are potentially able to be cured by surgery or radiation therapy. Ga 68 PSMA-11 also is indicated for patients with suspected prostate cancer recurrence based on elevated serum prostate-specific antigen levels. Ga 68 PSMA-11 is a radioactive diagnostic agent that is administered in the form of an intravenous injection.3

“The downside is that this is only available at the University of California, San Francisco, and UCLA currently,” Gomella said. “Regardless, it’s important that our colleagues know that this is a technology that is now available.”

Bladder Cancer

In January 2020, the FDA approved pembrolizumab (Keytruda) for the treatment of patients with Bacillus Calmette-Guérin (BCG)–unresponsive, high-risk, non–muscle invasive bladder cancer (NMIBC) with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.4

“What’s exciting about this approval is that it’s a systemic therapy, which is not delivered via intravesical administration,” Gomella said. “In that regard, it’s first in class.”

Gomella also discussed a type of gene therapy for patients who are BCG-unresponsive that is delivered intravesically—nadofaragene firadenovec, also known as rAd-IFN/Syn3.

A phase 3 multicenter study (NCT02773849) published in the January issue of Lancet Oncology demonstrated that the gene therapy was efficacious.5 About 53% of patients (n = 103) with carcinoma in situ (with or without a high-grade Ta or T1 tumor) had a complete response within 3 months of the first dose, and this response was maintained in 25 of 55 patients (45.5%) at 12 months, according to investigators. Micturition urgency (1%) was the most common grade 3/4 study drug-related adverse event, and there were no treatment-related deaths. The agent is currently being evaluated by the FDA.

Upper Tract Urothelial Carcinoma

In this setting, Gomella noted the approval of Jelmyto (mitomycin gel), which received FDA approval in April 2020. It is the first therapy to treat low-grade tract urothelial cancer (UTUC).6

Although the majority of urothelial cancers occur in the bladder, UTUC corresponds to a subset of urothelial cancers that arise in the lining of the kidney or the ureter. The gel is an alkylating drug, meaning it inhibits the transcription of DNA into RNA, stopping protein synthesis, and taking away the cancer cell’s ability to multiply.

“This gel has some interesting physical properties. At room temperature, it’s liquid, but when it warms, it becomes a solid,” Gomella said. “This is injected into the upper urinary tract through the bladder. It gives us an alternative treatment option for some patients who may otherwise require a nephroureterectomy.”

In addition to these advancements, the conference also will address the diagnostic molecular pathology of GU tumors and evolving strategies for diagnosis, proactive monitoring, and mitigation of treatment-related adverse effects.

REFERENCES
1. FDA approves olaparib for HRR gene-mutated metastatic castration-re-sistant prostate cancer. FDA. May 19, 2020. Accessed January 18, 2021. https://bit.ly/3oWxtf4
2. Shore ND, George DJ, Saad F, et al. HERO phase III trial: Results com-paring relugolix, an oral GnRH receptor antagonist versus leuprolide ace-tate for advanced prostate cancer. J Clin Oncol. 2020;38(suppl 15):5602-5602. doi: 10.1200/JCO.2020.38.15_suppl.5602
3. FDA approves first PSMA-targeted PET imaging drug for men with prostate cancer. FDA. December 1, 2020. Accessed January 18, 2021. https://bit.ly/3swKNsV
4. FDA approves pembrolizumab for BCG-unresponsive, high-risk non-muscle invasive bladder cancer. FDA. January 8, 2020. Accessed Jan-uary 18, 2021. https://bit.ly/3oYgj0q
5. Boorjian SA, Alemozaffar M, Konety BR, et al. Intravesical nadofara-gene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. 2021;22(1):107-117. doi:10.1016/S1470-2045(20)30540-4
6. FDA approves first therapy for treatment of low-grade upper tract urothelial cancer. FDA. April 15, 2020. Accessed January 18, 2021. https://bit.ly/39N0jYQ