Therapies in the Pipeline for Prostate Cancer
New potential medications may continue to expand the role of targeted agents.
In the United States, prostate cancer is one of the most common cancers, with nearly 250,000 new diagnoses projected for men in the United States in 2021.1 In recent years, many new therapeutic options have become available for patients with prostate cancer for improving outcomes.
An oral GnRH antagonist, relugolix (Orgovyx; Myovant Sciences and Pfizer Oncology), was approved as a once-daily oral option for patients based on the HERO study (NCT03085095),2 and the role of targeted agents has continued to expand in prostate cancer. Current FDA approvals of 2 PARP inhibitors, olaparib (Lynparza; AstraZeneca) and rucaparib (Rubraca; Clovis Oncology), based on the PROFOUND (NCT02987543) and TRITON2 (NCT02952534) trials, respectively, have provided a new therapeutic option for prostate cancer patients with BRCA mutations.3,4
New potential prostate cancer medications in the pipeline continue the expansion of potential targets.
FDA-approved drugs seeking new indications in prostate cancer
Cabozantinib and Atezolizumab
Cabozantinib (Cabometyx; Exelixis) is a tyrosine kinase inhibitor targeting VEGF, AXL, and MET as pathways to angiogenesis and regulation of immune suppression, among other targets. Atezolizumab (Tecentriq; Genentech) is a monoclonal antibody targeting programmed death ligand 1 (PDL1). Individually, both cabozantinib and atezolizumab have shown some activity in phase 1 trials in prostate cancer.5,6
Possible synergy of the 2 agents in combination was noted in a cohort of the phase 1b COSMIC-021 (NCT03170960) trial in metastatic castrate resistant prostate cancer (mCRPC), in patients having progression on enzalutamide (Xtandi; Astellas and Pfizer) or abiraterone acetate (Zytiga; Janssen Oncology). The overall objective response was 33% in the cohort of 44 patients with authors noting a tolerable safety profile. Subsequent to these findings, further accrual has taken place to expand this cohort.7 On last reporting, patients were receiving cabozantinib 60 mg daily along with atezolizumab 1200 mg every 3 weeks. Cabozantinib is supplied in 20-mg, 40-mg, and 60-mg tablets.8
Talazoparib (Talzenna; Pfizer Oncology), one of the most potent PARP inhibitors because of its induction of PARP1,9 has been approved as monotherapy in BRCA-mutated human epidermal growth factor receptor 2-negative metastatic breast cancers based on the EMBRACA trial (NCT01945775).10,11
The phase 3 TALAPRO2 trial (NCT03395197) is a 2-armed, randomized controlled trial comparing enzalutamide and talazoparib to enzalutamide monotherapy in mCRPC with a BRCA mutation and progression on prior antihormonal therapies.12 Results of the trial are pending publication, but this may broaden the scope of PARP inhibition in prostate cancer and address possible synergy in using a PARP inhibitor combined with an antihormonal agent, since prior studies investigated PARP inhibitors as monotherapy. The dose of talazoparib in the ongoing TALAPRO-2 trial is 0.5 mg taken once daily, with capsules coming in a 0.25-mg or 1-mg strength.10
Non-FDA Approved Medications Under Investigation in Prostate Cancer
Intravenous docetaxel (Taxotere; Sanofi) has been a well-established treatment option in prostate cancer since the TAX 327 trial (NCT01989676) demonstrated both a benefit in survival and improvement in quality of life, in 2004.13 Subsequent to establishing docetaxel as part of standard of care, many oral antihormonal and targeted agents have been approved.
ModraDoc006/r (Modra Pharmaceuticals) is an oral tablet formulation of docetaxel sharing the anti-tumor mechanism of its intravenous counterpart, promoting microtubule assembly while simultaneously inhibiting tubulin activity, which would stabilize microtubules.14 The bioavailability of oral docetaxel is diminished by both CYP3A4 and P-glycoprotein; as such, ModraDoc006/r has been formulated with ritonavir (Norvir; AbbVie), which inhibits both CYP3A4 and P-glycoprotein.15
M18MDP (NCT04028388) is an ongoing phase 2b trial comparing ModraDoc006/r to intravenous docetaxel in patients with mCRPC. Early trends indicate both arms have an impact on prostate-specific antigen (PSA) as well as the primary end point of radiographic progression-free survival, though these data are preliminary.16 In this trial, ModraDoc006/r tablets were administered weekly on days 1, 8, and 15 of 21-day cycles.
Onvansertib (Cardiff Oncology) is an inhibitor of polo-like kinase 1 (PLK1), which regulates mitotic functions and is highly upregulated in prostate cancer following castration. It is currently being studied in combination with abiraterone and prednisone (Rayos; Horizon) in a phase 2 study (NCT03414034) of patients with mCRPC upon development of resistance to abiraterone, defined as 2 consecutive rises in PSA levels.17
Although patients eventually demonstrate resistance to abiraterone after approximately 9 to 16 months of treatment, the hope is that onvansertib can prolong the efficacy of abiraterone. In phase 1 testing, transient and reversible hematologic effects were seen with onvansertib, and current studies are investigating the best dosing for future studies. The dosing schedules being investigated are as follows: 24 mg/m2 orally on days 1 to 5 of a 21-day cycle, 18 mg/m2 orally on days 1 to 5 of a 14-day cycle, or 12 mg/m2 orally on days 1 to 14 of a 21-day cycle.
Ceralasertib (AZD6738; AstraZeneca) inhibits ATR kinase activity, which is involved in DNA repair. A phase 2 study (NCT03787680) is currently investigating ceralasertib at a dose of 160 mg orally once daily on days 1 to 7 of 28-day cycle in combination with olaparib 300 mg orally twice daily days 1 to 28 in patients with mCRPC.18 Patients must have received either 1 previous line of therapy in the metastatic setting or a second-generation anti-androgen such as abiraterone, enzalutamide, or apalutamide within the hormone-sensitive phase of disease with progression while on therapy. The study started in October 2019 and its estimated primary completion date is November 2021.
Opaganib (Yeliva; RedHill Biopharma) inhibits sphingosine kinase-2 (SK2), which interferes with cell metabolism. It is currently being studied at a dose of either 250 mg or 500 mg orally, twice daily in combination with either abiraterone or enzalutamide in a phase 2 study (NCT04207255) of patients with mCRPC who have progressed on either enzalutamide or abiraterone.19 The study started in March 2020 and its estimated primary completion date is January 2022.
There are many targeted therapies in the pipeline for prostate cancer, with some therapies utilizing synergy between already FDA-approved medications. Other therapies are investigating novel potential targets. Although some of the results of these trials are pending, the outlook for patients with prostate cancer could be improved with so many new therapies in the pipeline.
Justin (JC) Liauw, PharmD, BCOP, is a clinical pharmacy specialist who works rounding with the medical team inpatient at the Miriam Hospital, as well as in outpatient oncology at the Lifespan Cancer Institute, a member of the Acentrus Specialty network of health systems, in Providence, Rhode Island.
Sarah E. Cabral, PharmD, BCOP, is a clinical pharmacist at Lifespan Specialty Pharmacy in Providence. She has spent the majority of her career serving the oncology patient population and currently specializes in the
care of patients with genitourinary cancer receiving oral anticancer therapy.
- Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71(1):7-33. doi.org/10.3322/caac.21654
- Shore ND, Saad F, Cookson MS, et al. Oral relugolix for androgen-deprivation therapy in advanced prostate cancer. N Engl J Med. 2020;382:2187-2196. doi:10.1056/ NEJMoa2004325
- de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration resistant prostate cancer. N Engl J Med, 2020;382:2091-2102. doi:10.1056/NEJMoa1911440
- Abida W, Patnaik A, Campbell D, et al. Rucaparib in men with metastatic castration-resistant prostate cancer harboring a BRCA1 or BRCA2 gene alteration. J Clin Oncol. 2020;38(32):3763-3772. doi:10.1200/JCO.20.01035
- Smith DC, Smith MR, Sweeney C et al. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol. 2013;31(4):412-9. doi:10.1200/JCO.2012.45.0494
- Petrylak D, Loriot Y, Shaffer D, et al. Safety and clinical activity of atezolizumab
in patients with metastatic castration-resistant prostate cancer: a phase I study. Clin Cancer Res. 2021;27(12):3360-3369. doi:10.1158/1078-0432.CCR-20-1981
- Agarwal N, Loriot Y, McGregor BA, et al. Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: Results
of cohort 6 of the COSMIC-021 study. J Clin Oncol. 2020;38(15):5564. doi: 10.1200/ JCO.2020.38.15_suppl.5564
- Cabometyx. Prescribing information. Exelixis, Inc; 2021. https://www.cabometyx. com/downloads/CABOMETYXUSPI.pdf
- Muvarak NE, Chowdhury K, Xia L, et al. Enhancing the cytotoxic effects of PARP inhibitors with DNA demethylating agents—a potential therapy for Cancer. Cancer Cell. 2016;30(4):637-650. doi:10.1016/j.ccell.2016.09.002
- Talzenna. Prescribing information. Pfizer Inc.; 2018. https://www.accessdata.fda. gov/drugsatfda_docs/label/2018/211651s000lbl.pdf
- Litton J, Rugo HS, Ettl J, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med 2018;379(8):753-763. doi:10.1056/ NEJMoa1802905
- Agarwal N, Shore ND, Dunshee C, et al. Clinical and safety outcomes of TALAPRO-2: A two-part phase III study of talazoparib (TALA) in combination with enzalutamide (ENZA) in metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2019;37(15):5076 (suppl) doi:10.1200/JCO.2019.37.15_suppl.5076
- Tannock IF, de Wit R, Berry W, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351(15):1502-1512. doi:10.1056/NEJMoa040720
- Taxotere. Prescribing information. Sanofi; 2020. https://drive.google.com/drive/fold ers/1VI4f24ehiExITJ9p2RL4e2fqKbU-ICoc
- Vermunt MA, Robbrecht DG, Devriese AL, et al. ModraDoc006, an oral docetaxel formulation in combination with ritonavir (ModraDoc006/r), in metastatic castration-resistant prostate cancer patients: A phase Ib study. Cancer Rep. 2021;e1367. doi: 10.1002/cnr2.1367
- Vaishampayan UN, Keesen M, Shore ND et al. Phase IIb trial of oral ModraDoc006/r as a tolerable and effective option in comparison with intravenous docetaxel in metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2021;39(6):132 (suppl). doi:10.1200/JCO.2021.39.6_suppl.132
- Einstein DJ, Choudhury AD, Saylor PJ, et al. A phase II study of onvansertib in combination with abiraterone and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 38;2020 (suppl; abstract TPS 266). doi:10.1200/JCO.2020.38.6_suppl.TPS266
- Targeting resistant prostate cancer with ATR and PARP inhibition (TRAP trial). ClinicalTrials.gov. Updated June 9, 2021. Accessed July 22, 2021. https://clinicaltrials. gov/ct2/show/NCT03787680.
- Addition of opaganib to androgen antagonists in patients with mCRPC. ClinicalTrials.gov. Updated August 3, 2020. Accessed July 22, 2021. https://clinicaltrials.gov/ ct2/show/NCT04207255