Olaparib in Men With High-Risk Biochemically-Recurrent Prostate Cancer Following Radical Prostatectomy, With Integrated Biomarker Analysis

The proposed study is an open-label single-arm phase II trial.

Eligible patients are those with non-metastatic biochemically-recurrent prostate cancer and a
PSADT of ≤6 months and a minimum PSA of 1.0.

After enrollment, patients will be treated with olaparib at the established dose of 300mg
tablets by mouth twice daily. Patients will be followed monthly with clinic visits, safety
labs (including CBC w/diff, Comp), PSA, and toxicity assessments. Treatment [with a minimum
drug exposure of 12 weeks] will be continued until PSA doubling from study entry (confirmed
with another measurement at least 4 weeks later), development of radiographic metastatic
disease, or toxicity requiring drug cessation. CT scans and NM bone scans will be performed
every 6 months for patients remaining on olaparib treatment.

This study will enroll up to 50 subjects. The study design will employ a stepwise adaptive
statistical plan, derived in part from Biankin et al, Nature 2015 Oct 15;526(7573):361-70.
The design is adapted from a multi-stage design, with interim stopping rules to determine
futility or need for enrichment of the study population.

The study will initiate with a two-stage design in an unselected population. The assumptions
for the trial of the unselected population are: null hypothesis of 0.1 PSA response rate and
alternative hypothesis of 0.3 for the unselected population. The first stage is 20 subjects.
If ≤2 subjects responds in the first stage, then unselected population study is halted for
futility and an assessment of DNA mutations present in the initial cohort will be undertaken.
If less than 3 subjects with a known/suspected deleterious mutation in the following genes
(ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C,
RAD51D, or other DNA repair genes) have been accrued in the first stage, then the trial will
proceed with enrichment. If 3 or more subjects with known/suspected deleterious mutation in
the genes of interest have been accrued, then the trial will proceed with enrichment, as long
as the response rate in that subset of subjects is ≥20%. In the case that 3 or more subjects
have been accrued, yet the response rate in that subset is <20%, then the trial is halted for
futility.

However, if ≥3 subjects among the first 20 respond, then additional 10 unselected subjects
are accrued. If ≥6 subjects respond out of 30 in the unselected population after the second
stage, then the null hypothesis is rejected in the unselected population and broad efficacy
will be concluded.

The trial proceeds to complete accrual of 50 subjects in order to better estimate PSA
response rate and strengthen data for correlative studies. If <6 respond, then the null
hypothesis is not rejected. Again, if less than 3 subjects with a known/suspected deleterious
mutation in the following genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL,
PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or other DNA repair genes) have been accrued in the
first and second stage combined, then the trial will proceed with enrichment. If 3 or more
subjects with those mutations have been accrued, then enrichment will again proceed as long
as the response rate in that subject of subjects is ≥20%.

Inclusion Criteria:

1. Histologic diagnosis of adenocarcinoma of the prostate

2. Prior local therapy with prostatectomy required, with available tissue from
prostatectomy specimen to send for genomic and transcriptomic testing.

3. Prior salvage or adjuvant radiation therapy is allowed but not mandated. Radiation
therapy must have been completed for at least 6 months.

4. Absolute PSA ≥1 ng/ml. Prior undetectable PSA post-prostatectomy is not required.

5. PSADT ≤6 months, based upon ≥3 consecutive measurements collected in the past 12
months, at least 4 weeks apart

6. No radiographic evidence of metastatic disease by CT scan and bone scan, performed
within the prior 4 weeks.

7. Serum testosterone ≥ 150 ng/dl

8. Participants must have normal organ and bone marrow function measured within 28 days
prior to administration of study treatment as defined below:

- Hemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days

- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

- Platelet count ≥ 75 x 109/L

- Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)

- Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT))
/ Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT))
<2.5 x institutional upper limit of normal. Note: Patients with elevations in
bilirubin, AST, or ALT should be thoroughly evaluated for the etiology of this
abnormality prior to entry and patients with evidence of viral infection should
be excluded.

- Patients must have creatinine clearance estimated using the Cockcroft

- Gault equation of ≥51 mL/min:

Estimated creatinine clearance = (140-age [years]) x weight (kg) serum creatinine
(mg/dL) x 72

9. Eastern Cooperative Oncology Group (ECOG) performance status 0-1

10. Male participants and their partners, who are sexually active and of childbearing
potential, must agree to the use of two highly effective forms of contraception in
combination [see appendix F for acceptable methods], throughout the period of taking
study treatment and for 3 months after last dose of study drug to prevent pregnancy in
a partner.

11. For enrichment stage of trial only (if necessary): Confirmation of a suspected/known
deleterious mutation in a gene of interest (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12,
CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or other DNA repair
genes) via CLIA certified testing.

Exclusion Criteria:

1. Prior ADT in the past 6 months. Prior ADT in context of neoadjuvant/adjuvant primary;
prior ADT for biochemical recurrence is allowed, as long as no ADT has been
administered in past 6 months and testosterone has recovered (>150 ng/dl). The total
duration of prior ADT should not exceed 24 months.

2. Prior oral anti-androgen (e.g. bicalutamide, nilutamide, enzalutamide, apalutamide),
or androgen synthesis inhibitor (e.g. abiraterone, orteronel) in the past 6 months.
5-alpha reductase inhibitor therapy (e.g. finasteride, dutasteride) is allowed, as
long as subject has been stable on medication for past 6 months.

3. Prior treatment with intravenous chemotherapy.

4. Involvement in the planning and/or conduct of the study

5. Participation in another clinical study with an investigational product during the
last 1 month.

6. Any previous treatment with PARP inhibitor, including olaparib

7. Resting ECG with QTc > 470 msec on 2 or more time points within a 24 hour period or
family history of long QT syndrome

8. Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin,
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg.
ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout
period prior to starting olaparib is 2 weeks.

9. Concomitant use of known strong CYP3A inducers (eg. phenobarbital, enzalutamide,
phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's
Wort ) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required
washout period prior to starting olaparib is 5 weeks for phenobarbital and 3 weeks for
other agents.

10. Myelodysplastic syndrome/acute myeloid leukaemia or with features suggestive of
MDS/AML.

11. Major surgery within 2 weeks of starting study treatment and patients must have
recovered from any effects of any major surgery.

12. Poor medical risk due to a serious, uncontrolled medical disorder, non- malignant
systemic disease or active, uncontrolled infection. Examples include, but are not
limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial
infarction, uncontrolled major seizure disorder, extensive interstitial bilateral lung
disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder
that prohibits obtaining informed consent.

13. Unable to swallow orally administered medication and patients with gastrointestinal
disorders likely to interfere with absorption of the study medication.

14. Immunocompromised patients, e.g., patients who are known to be serologically positive
for human immunodeficiency virus (HIV).

15. Known hypersensitivity to olaparib or any of the excipients of the product.

16. Known active hepatitis (i.e. Hepatitis B or C) due to risk of transmitting the
infection through blood or other body fluids

17. Whole blood transfusions in the last 120 days prior to entry to the study (packed red
blood cells and platelet transfusions are acceptable, for timing refer to inclusion
criteria no.10)