Updates in Precision Oncology in Prostate and Urothelial Cancer

Next generation sequencing has revolutionized the treatment of cancer. Molecular profiling can be either germline, identifying inherited genetic alterations, or somatic, characterizing genetic alterations that are not inherited. In prostate cancers, germline molecular profiling is recommended by guidelines as standard of care for high risk and metastatic cancer and somatic profiling for metastatic cancer.¹ In urothelial cancer, somatic molecular profiling is recommended for locally advanced and metastatic cancer,² although studies have identified potentially clinically actionable germline mutations.³ In addition to clinical use, recent breakthroughs and cutting-edge research in prostate and bladder cancer have identified potential novel impacts of next generation sequencing in prostate and bladder cancer.

Poly(ADP-ribose) polymerase (PARP) is an important protein in the DNA damage repair pathway, involved in repairing single strand breaks. PARP inhibitors induce synthetic lethality in cells with DNA damage repair alterations.⁴ In prostate cancer, the most common DNA damage repair mutations are BRCA2, responsible for 44 percent of all germline mutations and BRCA1, responsible for 7 percent of all germline mutations.⁵ Homologous recombination repair mutations are often hallmarks of aggressive disease. Olaparib and rucaparib are two PARP inhibitors that have shown efficacy in prostate cancer patients with DNA damage repair mutations.^6‑8 Unfortunately, not all eligible patients receive these therapies. Racial disparities have been observed, noting that despite white and black patients having similar rates of actionable genetic alterations, black patients are less likely to receive targeted therapy.⁹

Combining PARP inhibitors with novel hormonal therapies that target androgen receptor (AR) signaling represents another recent advance in treatment of prostate cancer. Androgen deprivation therapy has been shown to increase PARP expression.¹⁰ There is controversy regarding whether AR regulates DNA repair genes, however, and this induction is likely modest at best.¹¹ Three landmark studies have demonstrated efficacy in the combinations of olaparib and abiraterone (PROPEL),¹² talazoparib and enzalutamide (TALAPRO-2),¹³ and niraparib and abireratone (MAGNITUDE)¹⁴ in metastatic castrate-resistant prostate cancer (mCRPC). All three were positive studies with olaparib and abiraterone (HR 0.66 [95% CI 0.54-0.81])¹² and talazoparib and enzalutamide (HR 0.63[95% CI 0.51-0.78])^12,13 showing benefit in all treated patients. Even greater benefit was seen in patients exhibiting homologous recombination repair deficiency mutations, with reduction in hazard ratio to 0.50[95% CI 0.34-0.73] for olaparib and abiraterone¹² and to 0.45[0.33-0.61] for talazoparib and enzalutamide.¹³ Conversely, the MAGNITUDE trial separated patients with HRR mutations, among which abiraterone and niraparib demonstrated benefit (HR 0.73[95% CI 0.56-0.96]), but the HRR-negative cohort was discontinued for futility when no benefit was observed (HR 1.09[95% CI 0.7-1.59]).¹⁴

Based on this evidence, many thought leaders feel that these combinations should not be considered in unselected patients. In these studies, the combination provides maximal benefit in patients with BRCA alterations, leading to restrictions in FDA approvals to BRCA mutated mCRPC for the combinations of abiraterone and olaparib¹⁵ and abiraterone and niraparib.¹⁶ Talazoparib plus enzalutamide was approved for HRR-mutated mCRPC.¹⁷ Alternatively, the European Medicines Agency determined that the combination of talazoparib and enzalutamide should be extended to all patients with mCRPC who are not chemotherapy candidates, eliminating any restrictions based on molecular profiling.¹⁸ Novel biomarkers may also help determine which patients may benefit, including novel PET-based molecular imaging to determine PARP expression.¹⁹

The androgen signaling axis results in activation of AR and downstream transcription that drives development of prostate cancer. AR consists of four regions, the N-terminal domain, DNA-binding domain, hinge region, and ligand binding domain. Many prostate cancer therapies target AR via the ligand-binding domain, however, resistance eventually develops.²⁰ Reasons for this resistance include increased steroidgenesis, amplification of AR in tumor cells, upregulation of the glucocorticoid receptor, point mutations in the AR splice variant, point mutations in the ligand binding domain, methylation of HSD17B2, and variants in HSD3B1. Novel biomarkers are being developed to identify this resistance. Using an assay called EnhanceAR-Seq, genomic alterations in the AR enhancer that are implicated in this resistance have been detected by liquid biopsy with 100% positive predictive value and 78% sensitivity.²¹

Novel treatments are being developed to overcome this resistance. EPI-7386 is an oral N-terminal domain inhibitor that prevents dimerization of AR. This treatment was safe and well tolerated in a phase 1 study in mCRPC patients.²² ARV-110 is an oral AR Proteolysis Targeting Chimera (PROTAC) degrader that has also shown promise in mCRPC, especially in patients with T878 AR muations.²³ The splice variant AR-V7 has also been associated with lack of response to AR-targeting therapies and is considered another potential therapeutic target.

Immunotherapy has revolutionized the treatment of cancer, and mismatch repair deficiency has been established as a universal indication for immune checkpoint inhibition based on the KEYNOTE-158 study.²⁴ Mismatch repair deficiency has been demonstrated in only 2-5 percent of prostate cancer cases, however.²⁵ Prostate cancer has been considered a "cold" tumor, with low tumor mutation burden, however for mCRPC patients who exhibit high tumor burden, response to immunotherapy has been observed.^26,27 Neuroendocrine prostate cancer (NEPC), often characterized by loss of RB and overexpression of AURK, may be more amenable to immunotherapy. This will be evaluated in the phase II PLANE-PC trial (NCT04848337), which investigates the combination of lenvatinib and pembrolizumab in NEPC.²⁸

Biomarkers have been proposed to enhance prostate cancer response to immunotherapy. CD8 T cell density and interferon-γ gene signature both correlate with positive response.²⁹ DNA damage repair deficiency has also been implicated in immunotherapy response, likely secondary to increased neoantigen load.³⁰ Dual checkpoint inhibition with ipilimumab and nivolumab has been explored in patients with CDK12 inactivation with PSA responses observed.³¹ Neoantigen vaccines are in development to treat prostate cancer. Key components of vaccine development are neoantigen prediction, vector production, and delivery by electroporation. A phase I clinical trial evaluating one such vaccine, PROSTVAC-VF Tricom, demonstrated clinical responses in patients with high risk metastatic hormone sensitive prostate cancer, including in patients with low tumor mutation burden.³² Utilizing effector cells in the tumor microenvironment is the key to optimizing efficacy of immunotherapy in prostate cancer.

Bladder cancer is complex, consisting of heterogeneous underlying biology and mutation patterns. Gene expression profiling highlights this diversity and can be both prognostic and predictive. FGFR3 is an important gene frequently altered in urothelial cancer. In low grade papillary Ta cancer, FGFR3 alterations are present in 60 percent of cancers, but in only 15-20 percent of muscle invasive bladder cancers.³³ These alterations are more frequently present in luminal gene expression signatures. This gene expression signature is more chemosensitive and proliferative than stromal "p-53 like" signatures but more chemoresistant and less proliferative than "basal" signatures.^34‑36 Luminal tumors that harbor FGFR3 alterations are also considered "immune-cold" and therefore less likely to respond to checkpoint inhibition.³⁴

Erdafitinib is a potent small molecule pan-fibroblast growth factor receptor (FGFR1-4) inhibitor that is the only genomic biomarker driven therapy approved for metastatic urothelial cancer. This drug is taken up by lysosomes, resulting in sustained intracellular release, which may contribute to its long-lasting activity.³⁷ Erdafitinib received accelerated approval from the United States Food and Drug Administration in 2019 following the phase II BLC2001 study, in which overall response rate was 40% and tumor shrinkage was observed for most patients who received the standard 8 mg dose.³⁸ In the subsequent phase III THOR study, erdafitinib demonstrated superior median overall survival compared to standard of care chemotherapy, including taxanes, in patients with FGFR3 and FGFR2 alterations who progressed on platinum-containing chemotherapy (12.1 vs. 7.8 months, HR 0.64[95% CI 0.47-0.88], p = 0.005).³⁹

Antibody-drug conjugates (ADCs) represent another targeted approach in metastatic urothelial cancer. These conjugates consist of a cell surface targeting antibody, cleavable or hydrolysable linker, and chemotherapy payload.⁴⁰ Often, ADCs are internalized into the cancer cell and taken up by lysosomes prior to release of the cytotoxic payload. In addition to targeted delivery of cytotoxic therapy, there is a proposed "bystander effect" by which the ADC kills neighboring tumor cells that do not contain the targeted antigen.⁴¹

Enfortumab vedotin is a Nectin-4 targeting ADC with a cleavable linker and monomethylauristatin E (MMAE) payload. This has shown superior efficacy in front-line treatment of metastatic urothelial cancer when combined with pembrolizumab as well as monotherapy following progression on immune checkpoint inhibitor.^42,43 Sacituzumab govitecan is a Trop-2 targeting ADC with hydrolysable linker and topoisomerase 1 inhibitor payload. This drug has also demonstrated efficacy in patients who progressed following immune checkpoint inhibition in metastatic urothelial cancer.⁴⁴ Another ADC under investigation is disitimab vedotin, which combines a HER-2 targeting antibody with MMAE payload. This has demonstrated potential to treat HER-2 low and HER-2 positive metastatic urothelial cancer.⁴⁵ This novel drug class represents great advances in treatment of urothelial cancer, however caution is required due to toxicities, including rash and neuropathy with enfortumab vedotin and cytopenias and diarrhea with sacituzumab govitecan.

Precision oncology has significant implications for management of prostate and bladder cancer. Molecularly targeted treatments, including PARP inhibitors and erdafitinib, have provided novel therapeutic options for patients, as monotherapy and in combination with other standard treatments. Ongoing precision oncology research will identify new therapeutic targets as well as prognostic and predictive biomarkers to improve optimization to maximize efficacy with minimal toxicity.

JRB has received funding from EMD Serono for their speakers bureau and advisory board and from Pfizer for their advisory board. He also received consulting fees from AstraZeneca. He receives institutional funding from EMD Serono, Hoffman La-Roche AG, Seattle Genetics, Jounce Therapeutics, Bicycle Therapeutics, and Novita Pharmaceuticals.

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Thanks to the Binaytara Foundation for organizing the Precision Oncology Summit and to Dr. Pachynski, Dr. Siefker-Radtke, and Dr. Vaishampayan for presenting the material discussed in these conference proceedings.

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Concept and design: JB

Data acquisition: JB

Data analysis and interpretation: JB

Drafting of the manuscript: JB

Critical revision of the manuscript: JB

The author (JB) approved the final version of the manuscript and agrees to be accountable for all aspects of the work, in accordance with the International Committee of Medical Journal Editors criteria.

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