3702 PART XV The Prostate
Finally, two registrational placebo-controlled phase III trials of
custirsen are underway. The first study (SYNERGY) randomized 1022
patients with chemotherapy-naive mCRPC to receive standard
docetaxel versus the combination of docetaxel plus open-label
custirsen; overall survival was chosen as the primary end point in
this trial. This study failed to meet its primary end point (Chi et al.,
2017). The second study (AFFINITY) randomized 630 patients with
docetaxel-pretreated CRPC to either cabazitaxel alone or cabazitaxel
plus custirsen; the primary end point of this study was also overall
survival. Unfortunately, that study also failed to achieve its primary
end point, calling into question the future development of custirsen
in prostate cancer (Beer et al., 2017b).
Targeting DNA Repair
A new class of agents being explored for the treatment of metastatic
CRPC are the poly–ADP-ribose polymerase (PARP) inhibitors
(Christenson et al., 2018). PARP is an enzyme that is involved in
multiple aspects of DNA repair, particularly single-strand DNA repair,
and may rescue cells with deficiencies in homologous recombination
(which is the primary mechanism of double-strand DNA repair). In
several different cancers in which homologous recombination is
impaired, pharmacologic inhibition of PARP may result in “synthetic
lethality” and apoptosis of cancer cells (Farmer et al., 2005). PARP
inhibitors have proven particularly effective in ovarian and breast
cancer patients harboring germline and/or somatic mutations in
BRCA1 or BRCA2 and have already received FDA approvals in advanced
breast and ovarian cancers with inherited BRCA1/2 deficiencies.
Although PARP inhibitors do not appear to be effective in
unselected patients with advanced prostate cancer, the drugs may have
better activity in tumors harboring somatic and/or germline mutations
in DNA repair genes, especially inactivating mutations of homologous
recombination genes (e.g., BRCA1/2, ATM, PALB2, FANCA and other
Fanconi anemia genes). The prevalence of somatic DNA repair gene
mutations in metastatic CRPC appears to as high as 20% to 25%
(Robinson et al., 2015). To this end, olaparib (400 mg twice daily) was
recently tested in a study of men with heavily pretreated metastatic
CRPC (Mateo et al., 2015). Although the response rate to olaparib
was only 33% in the unselected population, an 88% response rate
was observed in men with germline or somatic mutations in one or
more DNA repair genes. In addition, PFS and overall survival were
superior with olaparib in the biomarker-positive patients compared
with biomarker-negative patients. Based on the results of this study,
the FDA has granted olaparib “breakthrough therapy” status for
the treatment of metastatic CRPC with germline and/or somatic
mutations in BRCA1/2 or ATM. Randomized studies of olaparib versus
second-generation hormonal therapy in metastatic CRPC patients
with mutated BRCA1/2 or ATM genes (e.g., the PROFOUND trial)
are currently underway. A number of other PARP inhibitors are
also being tested in advanced prostate cancer, including rucaparib,
niraparib, and talazoparib (Christenson et al., 2018). Toxicities of
PARP inhibitors include nausea, fatigue, myelosuppression, and a
1% risk of myelodysplastic syndrome or acute myeloid leukemia.
PALLIATIVE MANAGEMENT
Pain and Spinal Cord Compression
As in other disseminated malignancies, palliation of symptoms and
maintenance of adequate quality of life represent the most important
objectives in the management of advanced prostate cancer. Cancer-
related pain is undoubtedly the most debilitating symptom associated
with advanced-stage metastatic prostatic carcinoma. Prompt recogni-
tion of the various pain syndromes associated with this disease is
critical to accomplish effective control of this devastating symptom.
The most common pain syndromes and their respective therapeutic
considerations are summarized in Table 162.1. Focal bone pain in
patients with CRPC can be well controlled using external-beam
localized radiation therapy. In general, it is also recommended that
painful areas that are shown to be abnormal on bone scintigraphy
should be evaluated with plain radiographs or CT imaging to exclude
KEY POINTS: TARGETED TREATMENTS
• espite often promising phase results, phase trials
have failed to demonstrate the clinical utility of
angiogenesis inhibition in advanced prostate cancer.
• ecause of the reciprocal interactions bet een the P
Akt/mTOR pathway and AR signaling, dual inhibition of
both pathways concurrently will likely represent the most
fruitful therapeutic strategy. This is exemplified by the
ongoing phase III trial combining the Akt inhibitor,
ipatasertib, with abiraterone in mCRPC patients.
• abo antinib is a novel small molecule inhibitor of c et
and VEGFR2 with significant activity on CRPC bone
metastases, but it failed to meet its primary end points in
the COMET-1 and COMET-2 pivotal trials.
• ustirsen is an antisense oligonucleotide against clusterin
mRNA, which may play a role in reversing resistance to
taxane chemotherapies, but phase III trials were negative,
calling into question its role in the treatment of mCRPC.
• PA P inhibitors e g , olaparib, rucaparib, niraparib are
being explored in mCRPC patients with germline or
somatic mutations that result in inactivation of
homologous recombination DNA repair, which is present
in about 20% to 25% of advanced prostate cancers. PARP
inhibitors are not currently FDA approved for any prostate
cancer indication.
the presence of osteolytic lesions or pathological fractures. Such
considerations become even more important when the painful areas
affect extremities and weight-bearing sites.
Epidural metastasis is fairly common and is a potentially devastat-
ing complication of systemic cancer. In view of the propensity for
prostate cancer to metastasize to the vertebrae and paravertebral
regions, the incidence of epidural cord compression is particularly
high in this disease. Early diagnosis and treatment of epidural
metastasis is critical in preserving ambulation and bowel and bladder
function and aids in the management of back pain (Gabriel and
Schiff, 2004; Grossman and Lossignol, 1990). Epidural cord compres-
sions arising from vertebral bodies account for the majority of spinal
cord compressions; less frequently they are associated with soft-tissue
masses involving the paravertebral region. Most of these patients
have abnormalities on bone scintigraphs and/or abnormal findings
on radiography at the time of diagnosis. However, a deficit on
neurologic examination may be the only finding in patients who
exhibit soft-tissue epidural metastasis in the paravertebral region.
Spinal magnetic resonance imaging (MRI) is used routinely to
exclude the possibility of significant epidural disease, and it has
almost entirely replaced other methods such as CT myelography
and conventional myelography. The first therapeutic intervention in
patients with suspected or documented cord compression should
include the administration of high doses of intravenous glucocor-
ticoids. Dexamethasone at doses ranging from 16 to 100 mg daily
is most commonly used. Patients are often administered an intra-
venous “loading dose” of 10 mg of dexamethasone followed by 4
to 10 mg every 6 hours; the optimal steroid dose remains relatively
undefined. On improvement of symptoms, which can be accomplished
promptly with glucocorticoids, the steroid dose may be tapered down
throughout a 2-week to 3-week period.
Radiation therapy is often the mainstay of definitive treatment.
However, reports suggest that decompressive surgery followed by
radiation therapy may be superior to radiation therapy alone (Patchell
et al., 2005). To this end, surgery should be considered in patients
who have evidence of progressive signs and symptoms during radiation
therapy, develop or are seen initially with unstable pathological
fractures that require stabilization, or experience recurrence after
radiotherapy. In addition, the overall prognosis of the underlying
disease should be considered during the treatment selection. Che-
motherapy is rarely used to treat epidural cord compression during
the acute management of this complication.