Prostate Oncologic Therapy While Ensuring Neurovascular Conservation (POTEN-C)

This is a phase II randomized, multi-institution, open-label, patient and HRQOL endpoint
assessor blinded study evaluating the ability of neurovascular element sparing SAbR to
decrease erectile dysfunction. The study procedure is to reduce 2-year Expanded prostate
cancer index composite (EPIC) sexual domain score decline by 50% (-20 to -10), there by
improving potency preservation. This reduction is usually expected to observe in patients
undergoing the treatment stereotactic ablative body radiotherapy (SAbR) to 40-45 Gy with
rectal spacer +/- sparing of at least one side's neurovascular structures using
dose-painting.

Primary Endpoint:

• The Expanded prostate cancer index composite (EPIC) health-related quality of life (HRQOL)
instrument includes a sexual function domain, which is used to produce a composite score of
0-100 from 9 questions related to ability to achieve an erection with or without aids and
participate in intercourse. The primary endpoint will be the mean 24-month decline in EPIC
sexual function domain composite score.

Secondary Endpoints:

- Acute Genitourinary (GU) and Gastrointestinal (GI) toxicity is defined as grade 1-5
toxicity occurring prior to 270 days from the start of protocol treatment. It is graded
based on CTCAE v4.0.

- Delayed GU and GI toxicity is defined as grade 1-5 toxicity occurring prior to 270 days
from the start of protocol treatment. It is graded based on CTCAE v4.0.

- Non GU and GI toxicity up to six months post treatment.

- Biochemical failure Radiation therapy oncology group-American Society for Therapeutic
Radiology and Oncology (RTOG-ASTRO) definition (also known as Phoenix definition) -
Thus, when the Prostate Specific Antigen (PSA) rises by more than 2 ng/ml above the
lowest level (nadir) achieved after treatment, biochemical failure has occurred and the
date of the failure is recorded at the time the nadir plus 2 ng/ml level is reached.
Patients should be followed for a minimum of 5 years on this study to evaluate this
endpoint.

- Overall survival

- Disease-specific survival

- Clinical progression including local/regional and distant relapse

- HRQOL questionnaires for genitourinary, gastrointestinal, and hormonal domains (EPIC and
SF-12)

- Dosimetric comparison of neurovascular element sparing with rectal spacer on this
protocol versus without spacer in prior SAbR phase I-II protocol treated patients at
UTSW

- Dosimetric comparison of neurovascular element sparing according to quality of spacer
placement (maximum spacer distance at mid-gland and at apex), as assessed by study P.I.
using simulation MRI images.

- Biopsy positivity in area of dose sparing (i.e. PTV2-PTV1). To be evaluated only those
patients in BCR who merit per clinician judgement a biopsy.

Sample Size: To enroll 120 patients (60 patients in each treatment arm).

The sample size is estimated, first, assuming that neurovascular element sparing SAbR
(experimental arm intervention) will result in a mean 24 month decline in EPIC (HRQOL
instrument) sexual domain composite score of -20, as compared to a decline of -10 in a
standard SAbR without neurovascular element sparing. A total sample size of 102 patients (51
patients in each treatment group) achieves 80% power to detect this difference of 10 in EPIC
sexual domain composite score decline at 24 months after treatment, with an equal standard
deviation of 20 in both groups and at a two-sided significance level of 0.10, using a
two-sample t-test (effect size 0.50).

An attrition rate of EPIC sexual domain questionnaire completion at 2-years of 15% is
anticipated, based upon yields from multi-center prospective trials in prostate cancer
radiotherapy with EPIC HRQOL endpoints. A total of 120 patients will be accrued to account
for this 15% attrition rate.

Statistical Analysis: For the primary endpoint, a two-sided two-sample t-test will be used to
compare EPIC sexual function domain score composite declines at 24 months from treatment
between experimental SAbR arms with and without neurovascular sparing. Our sample size of 60
patients in each arm gives a calculated 80% power to detect a difference of 10 (considered
the minimally important difference for sexual domain) at a two-sided significance level 0.10,
assuming an equal standard deviation of 20 in both groups and allowing for 15% attrition in
survey completion. Secondary endpoints and their analysis methodology is further specified in
the protocol.

Inclusion Criteria:

- Appropriate staging studies identifying patient as American Joint Committee on Cancer
(AJCC) 7th edition clinical stage T1 (a, b, or c) or T2 (a, b, or c) adenocarcinoma of
the prostate gland. The patient should not have direct evidence of regional or distant
metastases after appropriate staging studies. See Appendix I for details on AJCC 7th
Edition staging criteria. Histologic confirmation of cancer will be required by biopsy
performed within 12 months of registration. T-staging may be assessed by
multi-parametric imaging alone if digital rectal examination was deferred.

- The patient's Zubrod performance status must be 0-2 (see Appendix II for definition).

- The Gleason summary score should be less than or equal to 7 [Grade group 1 (Gleason
3+3=6), group 2 (Gleason 3+4=7), and group 3 (Gleason 4+3=7) are allowed]. See
Appendix III for details on definitions. While a template biopsy is recommended, it is
not required in the case of MRI fusion biopsy performed on all dominant MR lesions
(defined as Prostate imaging - reporting and data system (PIRADS) v2 4-5).

- Baseline AUA symptom score ≤19 (see Appendix IV for questionnaire) without need for
maximum medical therapy (specifically, not on tamsulosin 0.8mg daily)

- EPIC sexual domain composite score 60-100 (see Appendix V)

- Multi-parametric MRI evaluation of the prostate is required for this study within 90
days of registration. Gross radiographic disease on MRI (defined as PIRADS v2 score
3-5) must be > 5mm at minimum distance from at least one side's neurovascular bundle,
which is typically the closest of the neurovascular elements to the prostate.

- The serum PSA should be less than or equal to 20 ng/ml within 90 days of registration.

- Study entry PSA must not be obtained during the following time frames: (1) 10-day
period following prostate biopsy; (2) following initiation of ADT or
anti-androgen therapy; (3) within 30 days after discontinuation of finasteride;
(4) within 90 days after discontinuation of dutasteride; (5) within 5 days of a
digital rectal examination.

- Ultrasound or MRI based volume estimation of prostate gland ≤ 80 grams. Cytoreduction
therapy (finasteride or dutasteride only) may be considered for those with >60 gram
size.

- All patients must be willing and capable to provide informed consent to participate in
the protocol within the 30 days prior to registration

Exclusion Criteria:

- Subjects with clinical (digital rectal examination) evidence of extraprostatic
extension (T3a) or seminal vesicle involvement (T3b). MRI evidence of
equivocal/potential but not definite extraprostatic extension is allowed, as long as
it is unilateral and not on the side of the gland proposed for neurovascular element
sparing. In equivocal cases of potential extracapsular extension on MRI only,
discretion is left to the treating physician.

- MRI evidence of gross disease (defined as PIRADS v2 score 3-5 lesions) ≤5mm of BOTH
neurovascular bundles, which are the most proximate of the neurovascular elements
planned for sparing on this protocol.

- Patients with all three intermediate risk factors (PSA >10 and ≤ 20, Gleason 7,
clinical stage T2b-T2c) who ALSO have ≥50% of the number of their template biopsy
cores positive for cancer are ineligible.

- Inability to undergo multi-parametric MRI.

- Evidence of metastatic disease. Note bone scan is not required for this study given
the low-intermediate NCCN risk cohort to be enrolled.

- Evidence of clinical nodal involvement of the pelvis. Biopsy is required for lymph
nodes over ≥1.5cm in short-axis measured size.

- No current ADT or anti-androgen therapy at time of registration is allowed. Further,
no more than 3 cumulative months of prior ADT or anti-androgen therapy is allowed. If
either has been used by the patient, there must be a demonstration of full
testosterone recovery (>280ng/dL serum blood level), EPIC sexual domain score ≥60, and
at least 1 month between demonstration of testosterone recovery and study registration
(any one measurement of testosterone recovery suffices).

- Testosterone ≤ 280 ng/dL (any one measurement >280 ng/dL suffices for inclusion)

- Subjects who have had previous pelvic radiotherapy or have had chemotherapy or surgery
for prostate cancer.

- Subjects who have plans to receive other concomitant or post treatment adjuvant
antineoplastic therapy while on this protocol including surgery, cryotherapy,
conventionally fractionated radiotherapy, hormonal therapy, or chemotherapy given as
part of the treatment of prostate cancer.

- Subjects who have undergone previous transurethral resection of the prostate (TURP) or
ablative procedures to the prostate for benign prostatic hyperplasia or other
conditions (i.e. cryotherapy, HIFU).

- Subjects who have baseline severe urinary symptoms, as defined by AUA symptom score
>19 (alpha-blocker medication allowed except if taking tamsulosin 0.8mg daily at
baseline which indicates compensated severe symptoms and also can affect sexual
function).

- Subjects who have a history of significant psychiatric illness that would confound
informed consent.

- Severe, active co-morbidity, defined as follows:

- Unstable angina and/or congestive heart failure requiring hospitalization within
the last 6 months

- Myocardial infarction within the last 6 months

- Acute bacterial or fungal infection requiring intravenous antibiotics at time of
registration

- Patients with active inflammatory colitis (including Crohn's Disease and
ulcerative colitis) currently requiring systemic steroids and/or systemic
immunosuppression are not eligible.

- Subjects with a known allergy to polyethylene glycol hydrogel (rectal spacer material)
or contraindication to spacer products (Duraseal or SpaceOAR)

- Subjects with uncontrolled coagulation disorder which cannot be controlled with
anticoagulants

- Men of reproductive potential who do not agree that they or their partner will use an
effective contraceptive method such as condom/diaphragm and spermicidal foam,
intrauterine device (IUD), or prescription birth control pills.

- Men who require erectile function medication or aid to achieve an erection sufficient
for intercourse. Ability to achieve erection sufficient for intercourse without
medication or aid at least once time in the month prior to registration is sufficient
for inclusion.

- Men who have clinically significant penile malformation (i.e. Peyronie's disease) or
history of penile implantation are excluded.

- If DRE is performed, patient may not have palpable disease on side of gland to be
planned for neurovascular sparing. Given the poor accuracy of DRE, such a finding
should be confirmed by MRI and/or biopsy to harbor actual disease before excluding a
patient on this basis.