Randomized Salvage Radiation Therapy Plus Enzalutamide Post Prostatectomy

Enzalutamide is a second-generation androgen receptor signaling inhibitor that significantly
prolongs survival in patients with metastatic castration-resistant prostate cancer who have
received prior docetaxel chemotherapy 35,36. Enzalutamide has demonstrated activity in cells
that overexpress the androgen receptor. Unlike previous androgen receptor blocker (ARB)
agents, Enzalutamide does not display any agonist properties and blocks translocation of the
ligand-receptor complex into the nucleus preventing DNA binding 33. Enzalutamide is an oral
agent that is generally well tolerated and does not require concurrent steroid
administration, which makes it an ideal candidate for combination with salvage radiation
therapy (SRT).

Finally, provocative preliminary Phase II data presented at the American Society of Clinical
Oncology (ASCO) 2013 by M. Smith and colleagues assessed the efficacy and safety of 25-weeks
(~6-mos) of enzalutamide alone in prostate cancer of all stages who had never received
hormone therapy; presenting with non-castrate testosterone levels ( 230 ng/dL). Enzalutamide
alone for 6-mos achieved a high PSA response rate with efficacy similar to castration, but
.in contrast to castration, bone mineral density (BMD) remained stable and metabolic
variables were not substantially impacted.

The trial described here differs from Radiation Therapy Oncology Group (RTOG) 96-01, RTOG
05-34 and RADICALS in several ways. First, the eligibility criteria are stricter; less
favorable patients have been selected. Second, short-term ARB is being tested, while in RTOG
96-01 and RADICALS long-term ARB of 2-years was examined. Finally, and most importantly, we
are testing the second generation ARB agent, enzalutamide, alone in combination with SRT as
opposed to RTOG 05-34 and RADICALS which use androgen deprivation (AD).

This trial is not intended to address the efficacy of SRT alone over observation. The
complete response rate (a drop in PSA to undetectable levels) after SRT is 70%-80% and
durable responses are observed in 30%-40% of patients. For these reasons, it is not feasible
or appropriate to randomize men between observation and SRT. The more important issue is
whether the proportion of durable responses is increased by altering the therapeutic
approach, such as the use of enhanced ARB using enzalutamide.

Inclusion Criteria:

- Willing and able to provide written informed consent and Health Insurance Portability
and Accountability Act (HIPPA) authorization for the release of personal health
information.

- Males aged 18 years of age and above

- Patients must have adenocarcinoma of the prostate gland

- Patients must have received primary treatment with radical prostatectomy.

- Patients must have evidence of biochemical (PSA) relapse after prostatectomy

- Patients must have PSA within study range

- Patients must have non-metastatic (M0) disease, as defined by a lack of metastases
seen on CT scan of the chest/abdomen/pelvis and whole-body radionuclide 99Technetium
(Tc) bone scan, (or sodium fluoride PET scan) taken within 3 months of study entry.

- Patients must have had node negative (pN0) disease found at the time of surgery.

- Patients must have non-castrate levels of serum testosterone levels within study
range.

- Patients must not have previously received hormonal therapy (LHRH agonist,
antiandrogen, or both), with the exception of neoadjuvant or adjuvant hormones given
in conjunction with prostatectomy.

- Patients must have Eastern Cooperative Oncology Group (ECOG)performance status of 0-1,
and life expectancy greater 3 years.

- Patients must have laboratory test results within the certain ranges

- Patients must be disease-free from prior malignancies for greater than 3 years, with
the exception of non-melanoma skin cancers and superficial urothelial cancers.

- Patients must have the ability to swallow the study drug whole as a tablet or capsule.

- Throughout study, male patient and his female partner who is of childbearing potential
must use 2 acceptable methods of birth control (1 of which must include a condom as a
barrier method of contraception) starting at screening and continuing throughout the
study period and for 3 months after final study drug administration or per local
guidelines where these require additional description of contraceptive methods.

- Throughout the study, patients must use a condom if having sex with a pregnant woman.

Exclusion Criteria:

- Currently active second malignancy

- Primary treatment with radiation therapy.

- Radiographic or clinical evidence of local-regional tumor recurrence,

- Concurrent use of other antiandrogens, estrogen-like agents, or 5a-reductase
inhibitors.

- Use of systemic corticosteroids equivalent to prednisone (inhaled corticosteroids are
permitted).

- Concurrent use of other anti-cancer agents or treatments.

- Serious concurrent medical illnesses (including uncontrolled major cardiac, pulmonary,
Child-Pugh C liver or psychiatric diseases) or active major infections (including HIV,
Hepatitis A-C).

- Clinically significant cardiovascular disease including:

- Myocardial infarction within 6 months of Screening visit.

- Uncontrolled angina within 3 months of Screening visit.

- Congestive heart failure (within certain ranges)

- History of clinically significant ventricular arrhythmias

- Prolonged corrected QT interval

- History of Mobitz II second degree or third degree heart block without a
permanent pacemaker in place.

- Hypotension within certain ranges

- Uncontrolled hypertension within certain ranges

- Medications which lowers seizure threshold.

- History of seizure or any condition that may predispose to seizure including, but not
limited to underlying brain injury, stroke, primary brain tumors, brain metastases, or
alcoholism. Also, history of loss of consciousness or transient ischemic attack within
12months of enrollment (Day 1 visit).

- Patients taking medications that may have adverse interactions with enzalutamide