Keywords
hormone-sensitive - metastatic - prostate
Introduction
In a proportion of prostate cancer patients, there is evidence of metastatic disease
at diagnosis or the disease recurs as distant metastasis despite standard curative
treatment. An Indian hospital-based study reported that ~70% of prostate cancer patients
had metastasis at diagnosis.[1] The upfront management of men with metastatic hormone-sensitive prostate cancer
(mHSPC) had been with only androgen deprivation therapy (ADT), for a long time, either
with medical or surgical castration.[2] However, this scenario has recently changed after the publication of phase III randomized
control trials that combine other agents with ADT upfront and clinicians now have
various options to choose from. Each of these agents such as docetaxel, abiraterone
acetate, enzalutamide, and apalutamide combined with ADT has shown significant survival
benefit over ADT in randomized clinical trials. There is a lack of direct evidence
to suggest the best choice as none of the trials include a head-on comparison between
the available options. Factors such as toxicity profile, cost, and physicians’ and
patients’ preferences are vital in choosing one of these options over the other. In
the present manuscript, we have proposed an algorithm ([Fig. 1]) for the management of patients with mHSPC from the currently available, most relevant
literature on the topic.
Fig. 1 Treatment algorithm. ADT, androgen deprivation therapy; BMD, bone mineral density;
mHSPC, metastatic hormone-sensitive prostate cancer; RT, radiotherapy.
Androgen Deprivation Therapy
Androgen Deprivation Therapy
ADT can be offered in the form of bilateral orchiectomy (surgical castration) or medical
castration. Bilateral orchiectomy may be appropriate when a rapid decline in testosterone
is needed (e.g., worsening obstructive urinary symptoms and imminent cord compression)
or when cost or compliance to medical castration is a concern. In medical castration
with gonadotropin-releasing hormone (GnRH) agonists, a flare in serum testosterone
may result from an initial short-term surge of luteinizing hormone (LH), worsening
the symptoms. Antiandrogens (e.g., flutamide and bicalutamide) used for 2 to 4 weeks
may be effective in preventing this flare phenomenon.[3]
[4] GnRH antagonist degarelix is not associated with this surge of LH and can be a substitute
to a GnRH agonist when a rapid fall in serum testosterone is necessary. Incidence
of severe cardiac adverse events may be lower with the use of degarelix compared with
GnRH agonists,[5] an ongoing prospective trial is comparing the risk of cardiovascular events with
the use of GnRH agonists and antagonists.[6] The newer oral agent relugolix that has shown better testosterone suppression and
cardiovascular safety profile in a phase III randomized trial compared with leuprolide
is another potential option for ADT.[7]
ADT has several side effects that can diminish the quality of life, which include
loss of lean body mass, obesity, sexual dysfunction, vasomotor instability, gynecomastia,
fatigue, cardiovascular, and metabolic abnormalities. Another concerning side effect
is bone demineralization, which can lead to osteoporotic fractures.[8]
[9] Intermittent ADT is a strategy to reduce these adverse effects by pausing ADT when
patients have responded to treatment and restarting at progression. A phase III intergroup
trial did not find intermittent ADT noninferior to continuous ADT in respect of overall
survival (OS).[10] In spite of the theoretical advantage, intermittent ADT is not recommended for patients
of mHSPC save for those with an elevated serum prostate-specific antigen (PSA) as
the sole manifestation of disseminated prostate cancer,[11] unless quality of life is the main expectation.
Docetaxel
The first evidence of benefit from a combination treatment was with docetaxel that
had previously improved OS in patients of metastatic castration-resistant prostate
cancer (mCRPC).[12]
[13] The CHAARTED trial that accrued 790 patients with hormone-naive metastatic prostate
cancer reported improved survival of patients with mHSPC when docetaxel was added
to ADT compared with ADT alone.[14] However, in a smaller study (GETUG-AFU15), docetaxel plus ADT did not improve survival
in patients of mHSPC and reported more toxicities.[15] This conflicting evidence was explained by the difference in the burden of disease
between the patient populations enrolled in these studies; they also differed in the
number of chemotherapy cycles used. In the CHAARTED study, the majority (65%) of the
patients had high-volume disease ([Table 1]). Those with high-volume disease had a significant OS benefit from adding docetaxel
to ADT (median OS 51.2 months vs. 34.4 months, hazard ratio [HR] = 0.63; 95% confidence
interval [CI]: 0.50–0.79; p < 0.001), but this was not evident in patients with low-volume disease (HR: 1.04; 95%
CI: 0.70–1.55; p = 0.86).[17] The arm C of the multiarm, multistage platform, STAMPEDE trial showed[18] a significant OS benefit for patients treated with the combination of docetaxel
and ADT (median OS 60 months in ADT plus docetaxel vs. 45 months in ADT only [HR:
0.76; 95% CI: 0.62–0.92]). Long-term survival results from the STAMPEDE trial reported
OS benefit for the combination of docetaxel with ADT in mHSPC (59.1 vs. 43.1 months,
stratified log-rank test p = 0.003, HR: 0.81; 95% CI: 0.69–0.95) irrespective of metastatic disease burden.
Improvements in OS, time to metastatic progression, and time to next treatment for
both low- and high-burden metastatic disease were reported in the updated analysis.[19] A meta-analysis on the data from the aforementioned trials reported survival benefit
in patients treated with docetaxel plus ADT (HR: 0.77; 95% CI: 0.68–0.87 [p < 0.001]), reaffirming upfront use of chemotherapy in mHSPC.[16]
Table 1
Stratification by metastatic disease burden
|
Trial
|
Definition
|
|
CHAARTED14
|
Defined as: (i) four or more bone metastases on high volume bone scan, including one
or more outside the vertebral bodies or pelvis, and/or (ii) visceral metastases
|
|
LATITUDE16
|
Defined as meeting at least two of three high risk criteria: (i) Gleason score >8,
(ii) presence of ≥3 lesions on bone scan, (iii) presence of measurable visceral lesions
|
However, patients receiving combination treatment with docetaxel and ADT had higher
rates of neutropenia, febrile neutropenia, and fatigue. Febrile neutropenia rates
among patients were 16% in GETUG-AFU 15, 13% in STAMPEDE, and 6% in CHAARTED trial.[20]
Abiraterone Acetate
Abiraterone acetate, an irreversible inhibitor of CYP17A1 which initially got approval
for the treatment of mCRPC,[21]
[22] reported OS benefit in mHSPC when added to ADT in two phase III trials, LATITUDE
and STAMPEDE.[23]
[24]
The LATITUDE trial enrolled 1199 patients with treatment-naive mHSPC with two or more
high-risk features ([Table 1]) and compared ADT plus abiraterone with ADT alone and reported significantly better
survival (HR: 0.66 [95% CI: 0.56–0.78]; p < 0.0001) in the abiraterone with ADT arm. Risk of radiographic progression was reduced
by 53% with the addition of abiraterone (HR: 0.47 [95% CI: 0.39–0.55]; p < 0.001). Abiraterone significantly prolonged time to pain progression, next antineoplastic
treatment, the start of cytotoxic therapy, PSA elevation (p < 0.001 for all comparisons), and next symptomatic skeletal event (p = 0.009). Most subgroups benefitted with abiraterone added to ADT with the possible
exceptions of the patients with Eastern Cooperative Oncology Group performance status
2, age of 75 years or more, or with a Gleason score of <8. In a retrospective observational
study from an Indian tertiary care cancer center, treatment outcomes were comparable
to phase III studies in patients treated with ADT combined with abiraterone.[25]
The STAMPEDE trial that randomized 1917 patients with HSPC (52% metastatic) to receive
abiraterone acetate with ADT (arm G) or ADT alone reported a 39% reduced death risk
(HR: 0.61; 95% CI: 0.49–0.75) in patients with mHSPC. Further, the risk of treatment
failure was also significantly reduced in patients receiving abiraterone (HR: 0.29
(HR: 0.29 , 95% CI: 0.25–0.34); p < 0.001). Interestingly, a post hoc subgroup analysis of OS in metastatic patients
included in STAMPEDE found survival benefit with coadministration of abiraterone and
ADT irrespective of risk (LATITUDE criteria) or volume (CHAARTED criteria); although
it required four times the number of high-risk patients to be treated to find the
OS benefit in the low-risk group.[26]
A prespecified direct comparison between the abiraterone and docetaxel arms of STAMPEDE
did not show a difference in OS, prostate cancer-specific survival, and symptomatic
skeletal events. Frequency of Grade 3 and 4 toxicities was comparable in both arms
but comprised different toxicities. Neutropenia of all grades and febrile neutropenia
occurred more frequently with docetaxel, while endocrine, cardiovascular, hepatic
disorders, and hypokalemia were more common with abiraterone.[27]
Novel Androgen Receptor Antagonists
Novel Androgen Receptor Antagonists
Enzalutamide, a second-generation androgen receptor inhibitor initially approved for
the treatment of CRPC,[28]
[29] has been explored as a treatment option combined with ADT in the mHSPC setting in
two phase III trials.[30]
[31]
Interim analysis of the ENZAMET trial showed a significant OS benefit in patients
treated with enzalutamide compared with those who received only ADT (HR = 0.67, p = 0.002). In the ARCHES trial, median radiographic progression-free survival (rPFS)
for the placebo plus ADT arm was 19.4 months (95% CI: 16.6, NR, not reached), whereas
median rPFS was not reached for the enzalutamide arm (HR: 0.39; 95% CI: 0.30, 0.50;
p < 0.0001). The enzalutamide arm also had a statistically significant improvement in
time to initiate a new systemic treatment (HR: 0.28; 95% CI: 0.20, 0.40; p < 0.0001). On December 16, 2019, the US Food and Drug Administration (FDA) approved
enzalutamide for patients with mHSPC.
In the TITAN trial,[32] a benefit for apalutamide was shown for men with both high-volume and low-volume
metastatic disease. There was a significant improvement in rPFS (HR: 0.48; 95% CI:
0.39–0.60), and the risk of radiographic progression or death was reduced by 52%.
In the apalutamide arm, the median rPFS was not reached and the same was 22.1 months
in the placebo arm. Importantly, apalutamide showed a significant improvement in OS
(HR: 0.67; 95% CI: 0.51–0.89), and reduced the risk of death by 33%. Median OS was
not reached for either apalutamide or placebo groups. Apalutamide was approved for
the treatment of mHSPC in the United States in September 2019.
In randomized trials, 0.5% of the patients receiving enzalutamide experienced seizures,
while fall and fractures, ischemic heart disease, and posterior reversible encephalopathy
syndrome remain other concerning side effects.[33] In the TITAN trial, 4% of the patients receiving apalutamide had ischemic cardiac
events. Apalutamide has also been associated with falls, fractures, and cardiac events
in clinical trial experience.[34]
Bone Health
Long-term ADT has been shown to adversely affect bone mineral density (BMD) and raise
pathological fracture risk in men. A large observational study found that prostate
cancer patients have significantly higher fracture risk when they receive ADT (19.4
vs. 12.6%; p < 0.001).[35] Metastatic prostate cancer patients have bone involvement in an estimated 90% of
cases,[36] and evidence suggests that men with metastatic prostate cancer have a higher incidence
of osteopenia and osteoporosis compared with age-matched control populations even
prior to starting ADT.[37] The National Institute for Health and Care Excellence UK guidelines recommend evaluation
of fracture risk for all men receiving ADT and that those found to have osteoporosis
should be offered treatment.[38] The European Association of Urology, European Society for Radiotherapy (RT) and
Oncology and International Society for Geriatric Oncology guidelines recommend BMD
assessment prior to starting long-term ADT.[39] In noncancer populations, FRAX,[40] a fracture risk assessment tool, is commonly used to calculate the 10-year probability
of major osteoporotic fracture (spine/ hip/forearm/humeral fractures) to warrant the
need for BMD assessment and/or treatment. The FRAX algorithm is useful in choosing
metastatic prostate cancer patients who require early bone-directed therapy.[41] However, there remains controversy regarding the benefit of using bone-directed
therapy in men with mHSPC as compared with mCRPC. The STAMPEDE trial, in which high
risk prostate cancer patients with and without osseous metastases were enrolled, the
addition of zoledronic acid (ZA) to standard care failed to improve OS, while the
addition of ZA to the arm that combined docetaxel to standard care did not show any
advantage in failure free survival, skeletal related events (SREs), or OS. In the
CALGB 90202, the use of ZA for HSPC was not associated with a decrease in SRE risk
compared with treatment initiation after progression to CRPC.[42]
Evidence with the use of denosumab, a fully human monoclonal antibody immunoglobulin
G 2 against Receptor activator of nuclear factor kappa-Β ligand (RANK-L), is inadequate
in mHSPC compared with mCRPC where its role is established.[43]
[44]
[45] Denosumab is FDA approved for the prevention of bone loss and fractures during ADT
based on a phase III study in patients with nonmetastatic prostate cancer receiving
ADT, where denosumab improved BMD by 6.7% and reduced fracture risk (1.5 vs. 3.9%)
compared with placebo.[46]
In view of lack of evidence to support the use of bisphosphonates or denosumab in
combination with androgen receptor targeted agents or chemotherapy in patients with
mHSPC, routine use of bone-directed therapy is not recommended, but in men with osteoporosis
or higher fracture risk detected prior to initiating ADT, such treatment should be
considered.
The National Osteoporosis Foundation guidelines[47] recommended daily calcium (1,000–1,200 mg) and Vitamin D3 (400–1,000 IU) supplementation
along with additional treatment for men aged 50 years or older with osteopenia (T-score
between 1.0 and 2.5 at the femoral neck, total hip, or lumbar spine by dual-energy
X-ray absorptiometry [DEXA] scan) and a 10-year probability of hip fracture >3% or
a 10-year probability of a major osteoporosis-related fracture >20%. In our practice,
we initiate treatment with ZA (5 mg IV annually) or with denosumab (60 mg subcutaneous
every 6 months) when the fracture risk derived from BMD and FRAX score (risk of hip
fracture >3%, or risk of major osteoporotic fracture >20%) necessitates drug therapy.
A baseline DEXA scan before the start of therapy and another after 1 year of therapy
is recommended to monitor treatment response.[48]
Role of Radiotherapy
The benefit of local therapy in conjunction with ADT for those presenting with mHSPC
has been a subject of debate. The role of local RT concurrent with ADT has been tested
in two randomized trials; among them, the phase III HORRAD trial randomized 432 men
with primary metastatic prostate cancer with bone metastases and a serum PSA >20 ng/mL
to ADT with or without external beam RT.[49] At a median follow-up of 47 months, median OS did not improve from the addition
of RT (45 vs. 43 months, HR: 0.90; 95% CI: 0.70–1.14); however, the addition of RT
prolonged the median time to PSA progression (median: 15 vs. 12 months, HR: 0.78;
95% CI: 0.63–0.97). An unplanned subgroup analysis suggested that men with fewer than
five metastases might have survival benefits (HR: 0.68; 95% CI: 0.42–1.10) when treated
with RT in conjunction with ADT.
Survival benefit for RT to the prostate for unselected men with newly diagnosed metastatic
prostate cancer was also not demonstrated in the phase III STAMPEDE trial,[50] but there was an improvement in failure-free survival (3-year failure-free survival
32 vs. 23%, HR: 0.76; 95% CI: 0.68–0.84). In a prespecified subgroup analysis, OS
benefit was seen with RT in the men with a low metastatic burden (CHAARTED definition)
at diagnosis (3-year survival 81 vs. 73%, HR for death 0.68, 95% CI: 0.52–0.90) but
not in those with a high metastatic burden (HR: 1.07; 95% CI: 0.90–1.28).
Pooled results of both trials found ~7% improvement in survival in men with fewer
than five bone metastases, along with an overall improvement in biochemical progression-free
survival (HR: 0.74; 95% CI: 0.67–0.82) and failure-free survival (HR: 0.76; 95% CI:
0.69–0.84).[51]
Imaging and Assessment during Treatment
Imaging and Assessment during Treatment
In the initial evaluation of men diagnosed with conventional imaging as mHSPC at presentation,
there may be some role of next-generation imaging (positron-emission tomography-computed
tomography [PET/CT], PET/magnetic resonance imaging [MRI], and whole-body MRI) to
clarify the burden of disease and this can help to choose either multimodality management
of oligometastatic disease or systemic anticancer therapy alone, but prospective data
to guide such decision are limited.[52]
Men with mHSPC who receive systemic therapy require periodic assessments to identify
signs and symptoms of disease progression, as well as the side effects of treatment
([Table 2]). Measurement of serum PSA at specific intervals is the mainstay of testing. The
current National Comprehensive Cancer Network (NCCN) guideline recommends testing
PSA every 3 to 6 months during treatment for metastatic prostate cancer.[53] A rise in PSA values, or development of new symptoms, is the cue for a radiologic
assessment. When PSA levels do not decline in response to therapy or rise, the adequacy
of castrate status (defined as serum testosterone <50 ng/mL) should be checked.[54]
Table 2
Drugs and periodic monitoring
|
Drug
|
Periodic monitoring
|
|
Abbreviations: BP, blood pressure; CBC, complete blood count; ECG, electrocardiogram;
LFT, liver function tests.
|
|
Docetaxel
|
CBC and differential, LFT before each cycle
|
|
Abiraterone acetate+prednisolone
|
Baseline: CBC and differential, LFT, creatinine, glucose, electrolytes. For the first
three cycles: monitor blood pressure, serum potassium, LFT, every 2 weeks. Before
each outpatient visit (every 4 weeks): CBC and differential, LFT, creatinine, glucose,
electrolytes, regular monitoring of BP
|
|
Enzalutamide
|
Baseline: CBC and differential, creatinine, electrolytes, blood pressure, ECG
Before each outpatient visit: blood pressure, serum creatinine, electrolytes, ECG
|
Genetic Testing in Prostate Cancer
Genetic Testing in Prostate Cancer
It is important in prostate cancer to address the inherited component. A family history
of prostate cancer and/or other cancers (e.g., breast cancer diagnosed at an age younger
than 50 years, male breast cancer, ovarian cancer, colorectal cancer, pancreatic cancer,
and melanoma) may be associated with an increased risk of heritable prostate cancer.
The St. Gallen Advanced Prostate Cancer Consensus Conference 2017[55] and the Philadelphia Prostate Cancer Consensus Conference 2019[56] have addressed the issues of genetic counseling and genetic testing for prostate
cancer. The Philadelphia guidelines recommend genetic testing for all men with metastatic
prostate cancer and for those with a family history of cancer with gene panels wherever
feasible, which should include BRCA1/2 and DNA mismatch repair genes. The NCCN prostate
cancer guidelines[53] recommend offering genetic testing to men with a personal history of high- or very
high-risk regional or metastatic prostate cancer, or localized disease with intraductal
histology, as well as a family history of high-risk germline mutations (e.g., BRCA1
and BRCA2, Lynch mutation, Ashkenazi Jewish ancestry), or to those with a strong family
history of cancer. Clinical trials of poly-adenosine diphosphate-ribose polymerase
inhibitors have shown promising responses in men with germline or somatic mutations
in BRCA2, BRCA1, ATM, CHEK2, PALB2, and in other homologous recombination DNA repair
genes.[57]
[58] Olaparib and rucaparib have been approved by the FDA for men with mCRPC harboring
these mutations. On the other hand, advanced prostate cancer patients with loss of
DNA mismatch repair may benefit from treatment with immune checkpoint inhibitors.
However, these genetic components do not currently have any implications for the treatment
of mHSPC.
How to Choose One Option
The choice between chemohormonal therapy and combined androgen receptor-targeted therapy
(abiraterone or enzalutamide or apalutamide) is difficult, owing to the similar efficacy
outcomes ([Table 3]) in cross-trial comparisons. Differences ([Table 4]) in toxicities and costs rather than the subtle differences in efficacy end points
might, at times, guide selection among the many choices approved in the first-line
treatment of mHSPC. Docetaxel appears to be the most cost-effective and efficient
approach in combination with ADT for men with high-volume mHSPC; it is given for a
relatively shorter period of time—18 weeks with reversible albeit severe short-term
chemotherapy toxicities. However, in men with low-volume disease, the evidence of
benefit from adding docetaxel has been conflicting. Unfortunately, similar concerns
with evidence of clear benefit in low-volume disease remain with abiraterone as well
since its indication in low-volume disease is based on a post hoc analysis of STAMPEDE
that was not powered to find an OS benefit for the low-risk population. A cost-effectiveness
analysis from the US report docetaxel is a more cost-effective option than abiraterone
in the treatment of mHSPC.[59] Abiraterone is recommended daily until disease progression with a median time on
treatment of ~33 months and is expected to be costlier for our population. Patient
preferences and comorbidities often help in the decision-making process. Docetaxel
usually is preferred for patients who wish for a shorter treatment time. Patients
with preexisting hypertension, hepatic derangement, and metabolic abnormalities may
not be suitable candidates for abiraterone. Further, there is nothing to suggest that
abiraterone offers any benefit in the population considered ineligible for docetaxel—those
with poor performance status and the elderly, as a benefit in these subgroups was
unclear in the LATITUDE trial. Enzalutamide, the new entrant in this setting, has
proven to be effective for both low- and high-volume disease and is an attractive
option for those wishing to avoid chemotherapy and steroids. The unique adverse events
with enzalutamide such as falls, seizures, syncope, cognitive, and mental impairment
warrant caution while selecting patients. In general, patients who wish to avoid chemotherapy
at all costs and wish to minimize hospital visits should be offered an androgen receptor-targeted
therapy. In absence of prospective evidence, the question of whether we should add
docetaxel or abiraterone to ADT in patients with low-volume or low-risk mHSPC remains
a difficult one and such treatments should be offered with caution. Patients of mHSPC
with a low burden of bone metastases (four or fewer bone metastases, with none outside
the vertebral bodies or pelvis) and no visceral metastases may be offered RT to the
prostate in conjunction with systemic therapy. Finally, there are groups of patients
who may do well with ADT alone, even intermittently, sometimes for many years. The
ultimate choice for an individual patient largely depends on the oncologist elaborating
risks and benefits of each available option while considering the patient’s comorbid
conditions, access to treatment, financial aspects, and preference.
Table 3
Comparison of overall survival of trials (not head-to-head) in first-line treatment
of metastatic hormone-sensitive prostate cancer
|
Agent
|
Docetaxel
|
Abiraterone
|
Enzalutamide
ENZAMET30
|
Apalutamide
TITAN32
|
|
Study
|
CHAARTED14
|
STAMPEDE18,19
Arm C M1 patients
|
LATITUDE23
|
STAMPEDE24
Arm G M1 patients
|
|
Abbreviations: HV, high volume; LV, low volume; mHSPC, metastatic hormone-sensitive
prostate cancer; OS, overall survival.
Figures are hazard ratios with 95% confidence intervals from select phase III trials
in the upfront treatment of mHSPC.
|
|
OS
|
57.6 vs. 47.2 months
|
59.1 vs. 43.1 months
|
53.3 vs. 36.5 months
|
0.61 (0.49–0.75)
|
0.67 (0.52–0.86)
|
0.67 (0.51–0.89)
|
|
|
|
|
|
|
|
|
0.72 (0.59–0.89)
|
0.76 (0.62–0.92)
|
0.66 (0.56–0.78)
|
–
|
–
|
–
|
|
10.4 months
|
16 months
|
15 months
|
|
|
|
|
OS-HV
|
0.63 (0.50–0.79)
|
0.81 (0.64–1.02)
|
0.62 (0.52–0.78)
|
0.60 (0.46–0.78)
|
0.80 (0.59–1.07)
|
0.68 (0.50–0.92)
|
|
OS-LV
|
1.04 (0.70–1.55)
|
0.76 (0.54–1.07
|
0.72 (0.47–1.10)
|
0.64 (0.42–0.97)
|
0.43 (0.26–0.72)
|
0.67 (0.34–1.32)
|
Table 4
Comparison of unique factors and toxicities between upfront options
|
Docetaxel
|
Abiraterone
|
Enzalutamide
|
|
Length of treatment
|
Shorter
|
Longer
|
Longer
|
|
Abbreviations: CNS, central nervous system; PRES, posterior reversible encephalopathy
syndrome.
|
|
Finances
|
Relatively inexpensive, likely to be covered by insurance
|
Costlier, likely to be out of pocket
|
Costlier, likely to be out of pocket
|
|
Rs. 10,000–15,000 per cycle for 6 cycles
|
Rs. 10,000 and above per month
|
Rs. 20,000 and above per month
|
|
|
|
|
|
|
|
|
Salient toxicities
|
Neutropenia, peripheral neuropathy, alopecia
|
Liver enzyme elevation, hypokalemia, hypertension
|
CNS-seizure, PRES, cognitive, falls, and fractures
|
|
|
|
|
|
Disease burden
|
High
|
High
|
Any
|
|
Steroid
|
Not required
|
Required
|
Not required
|
What I Follow in My Practice
What I Follow in My Practice
Most of the patients do present to our center with PSA, histopathology, and some imaging
(mainly MRI pelvis and bone scan). I generally review histopathology at our center
as per the institutional policy unless the report is from a reputed cancer center
or oncopathologist. If the available imaging already suggests metastatic disease,
I do not advise Ga prostate-specific membrane antigen (PSMA) PET/CT I use CT scans
of the thorax, abdomen, pelvis, and bone scan to assess metastatic disease volume.
For patients who present with PSA rise after past curative treatment, I prefer PSMA
PET/CT scan. I discuss medical and surgical castration with my patients and the cost
of treatment is often the main deciding factor between the two.[60] I recommend a baseline BMD before starting ADT. If the FRAX score is suggestive
of a high risk of fracture, they are offered ZA 5 mg once a year. For high-volume
disease, I discuss with the patients all three options (ADT with docetaxel or abiraterone
or enzalutamide). For patients with low-volume disease, I discuss ADT and local RT,
and ADT with one among enzalutamide, docetaxel, or abiraterone. I follow current genetic
testing guidelines in prostate cancer and discuss germline mutation testing for all
patients of mHSPC.
Conclusion
The oncologist’s armamentarium for treating mHSPC is rapidly expanding as newer evidence
demonstrates that combination therapy with one among docetaxel, abiraterone acetate,
enzalutamide, or apalutamide provides a significant OS benefit when compared with
ADT alone. The availability of many options with unique toxicity profiles allows oncologists
flexibility in choosing the right option for individual patients. We await the results
of ongoing randomized studies of darolutamide[61] or further intensification of treatment[62]
[63] to provide further guidance for clinicians. For now, it is rational to conclude
that upfront combination approaches are the new standard of care for men with mHSPC,
and some patients with low volume disease may benefit from the addition of RT, while
ADT alone remains an option only in patients who are either not fit for the combination
options or have unacceptable toxicities.
