Authors: Muzzammil Ahmadzada1, Waqas Haque2, and Muhammad A Saeed3
Affiliations: 1Johns Hopkins University; 2University of Texas Southwestern Medical School; 3 Zanvyl Krieger School of Arts and Sciences, Johns Hopkins University
Disclosures: The authors have no financial conflicts of interest.
The first section of this article briefly explains prostate cancer and the technology that the ARV-110 drug employs. The second section overviews the early clinical results collected, and the final section briefly analyzes the company Arvinas’ performance on the stock market.
What is Prostate cancer, and how does PROTAC technology combat it?
Prostate cancer is the most prevalent cancer that presents in men, next to skin cancer, especially over the age of 65.1 Studies show that about 1 in 9 men will be diagnosed with prostate cancer in their lifetime, with 1 in 41 men dying from it.1 Prostate cancer occurs in the prostate, a walnut-sized gland in men that produces the seminal fluid that nourishes and transports sperm.2 In early stages, prostate cancer may cause little to no signs or symptoms. Once advanced, an individual might experience trouble urinating, decreased force in the stream of urine, blood in semen, discomfort in pelvic area, bone pain, and erectile dysfunction.2
When detected in early stages, prostate cancer is manageable, with treatment options such as observation and surveillance, surgery, radiation therapy, cryotherapy, hormone therapy, chemotherapy, immunotherapy, and targeted therapy available.1 However, there are limitations and side effects to many of the treatment options, oftentimes leading to the combination of one or more treatments or switching from one to another.1
In recent times, a new technology termed proteolysis targeting chimera (PROTAC) has been developed for inducing protein degradation by a targeting molecule. This happens through the use of E3 ubiquitin ligase, which normally functions to tag proteins for degradation, including potentially harmful or misfolded ones, via the deposition of chains of ubiquitin molecules.3,4 Once tagged with ubiquitin, the cell’s proteasome recognizes the protein and degrades it. This technology is very promising due to the fact that it involves natural protein degradation, targets the proteins that are considered “undruggable” or out of drugs’ reach, has multiple routes of administration (infusion and injection), and has successfully penetrated the blood-brain barrier in preclinical studies.5
Arvinas, a clinical-stage biopharmaceutical company founded in 2013, is currently developing ARV-110, a PROTAC protein degrader that targets the androgen receptor (AR) on cells. The company intends to combat metastatic castration resistant prostate cancer (mCRPC) that progresses despite existing therapies.6 While other companies and drugs have sought to inhibit the AR on cancer cells, Arvinas’s mission is to change the treatment paradigm for prostate cancer by completely destroying the AR.6
The reason Arvinas has devoted its attention to destroying the AR instead of inhibiting them is because the current standard of care treatments for mCRPC, enzalutamide and abiraterone, have not been beneficial for around 25% of patients.6,7 For the other three-fourths of patients who do benefit, many of them eventually develop resistance to treatment. Resistance mechanisms include increased levels of androgen production, increased AR gene and enhancer expression, and/or AR point mutations.6
Instead, ARV-110 utilizes the cells innate ability to degrade proteins to effectively destroy AR proteins that are greatly responsible for prostate cancer. PROTAC protein degraders can degrade many copies of the target protein, overcoming increases in target expression and mutations that may arise in the AR.6,7
What are the recent results of the ARV-110 trials?
In peclinical studies, ARV-110 displayed promise by demonstrating a similar prostate-specific antigen (PSA) reduction rate as enzalutamide, but at lower doses. PSA is a popular serum marker for prostate cancer. As illustrated in the figure below, in vivo models of acquired and intrinsic resistance to enzalutamide, ARV-110 inhibited tumor growth by 70% and 100%, respectively.8
The Phase 1 trial had enrolled a particularly extensively pre-treated population of patients, each of whom had gone through chemotherapy, enzalutamide, and abiraterone. Despite all these prior treatments, ARV-110 demonstrated the first evidence of antitumor activity in this “difficult-to-treat” patient population, reported the Chief Medical Officer at Arvinas.7
Initial Phase 1 efficacy data for ARV-110 were presented at the American Society of Clinical Oncology conference (ASCO). The presentation included data for ARV-110 in 22 patients with progressive mCRPC and 20 evaluable from the first four dose-escalation cohorts – 35 mg (n=3), 70 mg (n=4), 140 mg (n=5), and 280 mg (n=8). All patients in the trial had a previous history of treatment, with 77% of patients having received both Xtandi (antiandrogen medication) and Zytiga (a hormone-based chemotherapy), and 77% having received prior chemotherapy.6
As of April 20, 20 patients were evaluated for PSA response, including 12 patients treated in the two highest dosage groups. Circulating tumor NA (ctDNA) analysis for 5 showed AR forms not degradable by ARV-110 in preclinical studies (i.e. L702H point mutations and AR-v7 splice variants). In the remaining 7 patients, two achieved confirmed PSA responses that remain ongoing with additional follow up, suggesting that the tumor was not spreading.6 One patient displayed a 74% decline from baseline in PSA and remained without progression after 30 weeks, but did not have measurable disease at baseline for assessment by Response Evaluation Criteria in Solid Tumors (RECIST). The second patient had both a sharp decline in PSA response (97% from baseline) and a confirmed RECIST response (80% decrease in tumor mass) and remained without progression for 18 weeks. Both of these responses were in patients taking 140 mg doses of ARV-110. In fact, the tumors in both patients have H875Y and T878A point mutations in AR, which are known to be resistant to other standards of treatment.6
ARV-110 also displayed PSA reductions in other patients in the cohort, but they did not meet the 50% reduction threshold.6 During the trials, 2 patients experienced a drug-drug interaction that led to acute renal failure in one patient, and a Grade 3 AST/ALT elevation in the other. Follow up experiments led scientists to discover the clash between ARV-110 and rosuvastatin (ROS), seeing as ROS concentrations were elevated in both patients. Subsequent studies revealed that ARV-110 inhibits breast cancer resistant pump (BCRP) transporter, of which ROS is a substrate. Upon correction, no more side effects were experienced.6
Dose escalation and enrollment continues, with a cohort initiating a dosing of 420 mg as recently as May 2020. The expansion of the Phase 1/2 trial is expected to begin once the recommended dose for Phase 2 has been determined. They will continue to measure efficacy in terms of PSA reduction and overall RECIST response in patients with measurable disease. Arvinas plans to provide updated information on the ARV-110 Phase 1/2 study by the end of 2020.6
What is Arvinas’ stock performance?
A brief analysis of Arvinas’ (ARVN) performance on the stock market shows great volatility. As of the past 52 weeks, ARVN stock has had a 52-week high of $61.57 USD per share, with the 52-week low being $15.19 USD.9 This difference of roughly $45 USD reflects the turbulent position shareholders and investors have been in, due to promising preclinical results followed by relatively underwhelming results in Phase 1. Whether the results were truly disappointing or not is debatable, but the extreme volatility of ARVN stock price is likely attributable to the low response in patients (only approximately 10% showing more than 50% PSA reduction)6, especially considering the fact that the current price of a share of ARVN (at the time of this article being written, August 2020) is $25.40, less than half of the 52-week high of $61.57. If one believes that the drug holds significant promise, it might be a good time to start purchasing Arvinas stock.