- Despite progress in the treatment of metastatic castration-resistant prostate cancer in the past 10 years, we are still seeing patients for whom second-generation hormonal agents initially work, only to cease effectiveness, leading to rapidly progressive, poorly differentiated cancer that is difficult to treat.
- We must set realistic expectations and educate patients and families on the variety of therapeutic options for prostate cancer treatment and their limitations, efficacy, and toxicities.
- Alternating effective therapies to optimize toxicity and potentially maintaining prolonged efficacy by delaying resistance is worth investigating.
Recently, I saw three patients with metastatic prostate cancer who had been on an androgen receptor axis–targeted (ARAT) therapy and whose disease had responded for a duration ranging from 1 to 3 years. Each of these patients had now progressed and presented with liver metastases. This is a newly emerging case scenario in medical oncology offices caring for patients with advanced prostate cancer. We frequently see patients present with aggressive, rapidly progressing prostate cancer and visceral metastases. The management dilemma that these cases present is of a perplexing magnitude. Most of these men have done fairly well on a second-generation hormonal agent, so both the patient and physician are lulled into a false sense of security that the temporary reprieve provides. Then the bubble bursts, and the patient has a rapidly progressive, poorly differentiated cancer that is incredibly hard to treat. Sometimes the patient may be too sick to tolerate chemotherapy, and only a minimal chance of response can be predicted. Bone marrow metastases that induce cytopenias, presence of synchronous cranial metastases, or impaired liver function are additional hurdles facing patients who are being considered for the next avenue of therapy.
Contrast this with the symptomatic patient with diffuse bone metastases whom we treated a few years ago who got a welcome, but again temporary, reprieve from the morbidity of prostate cancer. Why then, despite all the advances within prostate cancer, are we getting this sense of frustration? The reasons for this phenomenon are multifactorial and include the following:
- Patient and physician expectations have escalated to make chemotherapy administration taboo in metastatic prostate cancer,
- Lead-time bias from early detection of metastases by advances in imaging,
- Easily tolerated therapies that prompt the use of effective treatments in the asymptomatic phase of metastatic disease,
- Patient and physician reluctance to switch therapies too soon,
- The medical oncologist’s delayed involvement in prostate cancer care, and
- Underestimating the lethal and aggressive forms of metastatic prostate cancer.
It is imperative to adopt measures to address these problems and continue the upward trajectory of outcomes in advanced prostate cancer. If patients have a rapid prostate-specific antigen (PSA) doubling time, then different therapeutic options should be discussed. Oncologists must set realistic expectations and educate patients and families on the variety of therapeutic options and their limitations, efficacy, and toxicities. Alternating effective therapies to optimize toxicity and potentially maintain prolonged efficacy by delaying resistance is worth investigating. Periodic imaging studies to assess disease status and not relying entirely on PSA for monitoring are important. In addition, development of novel strategies continues to be essential in the treatment of metastatic castration-resistant prostate cancer (mCRPC).
Novel Targets in Prostate Cancer
Hormone therapy–based targets
Multiple novel hormone agents are in various stages of development. Some of them, such as ODM-201 (NCT02200614) and ARN-509 (SPARTAN trial; NCT01946204), are in double-blind, placebo-controlled phase III trials to evaluate efficacy in non-mCRPC. The addition of ODM-201 is also being evaluated in metastatic hormone-sensitive disease (NCT02799602). ARAT therapies, such as enzalutamide, ODM-201, and TAK-700, are also being tested in randomized trials in the metastatic hormone-sensitive setting.1
Resistance to androgen receptor (AR)–targeted therapies has been commonly associated with either AR amplification or splice variant or gain-of-function mutations.2 EPI-506 is a small-molecule N-terminal domain inhibitor that has demonstrated preclinical inhibition of AR, including splice variants such as AR-V7, and is currently in phase I clinical trials. ASN-001 is a CYP17 lyase inhibitor with selective activity against the testosterone production pathway and, hence, does not require steroid coadministration. This agent is also currently undergoing clinical trial testing.3
Cabazitaxel therapy was compared with docetaxel in the frontline setting of mCRPC with no difference in overall survival (OS; median of 25.2 months with cabazitaxel and 24.3 months with docetaxel) and the expected distinct toxicity profiles.4 Cabazitaxel demonstrated a response rate of 42% compared with 31% with docetaxel. Cabazitaxel at a dose of 20 mg/m2 showed favorable toxicity, with the lowest incidence of cytopenias, neuropathy, and alopecia within the three arms (docetaxel 75mg/m2, cabazitaxel 25mg/m2, and cabazitaxel 20 mg/m2, every 21 days as an IV infusion).5
Because docetaxel is now being used in hormone-sensitive metastatic prostate cancer, cabazitaxel is likely to emerge as the default standard for chemotherapy in mCRPC. Phase III trial data indicate that cabazitaxel at a dose of 20 mg/m2 can improve toxicity without compromising efficacy and suggest that this should be the preferred starting dose. Platinum-based chemotherapy is also a valid option in mCRPC, especially if neuroendocrine features are noted or if docetaxel and cabazitaxel are not feasible because of hepatic dysfunction. The combination of cabazitaxel and carboplatin was well tolerated and showed promising efficacy with a response rate of 52% in patients with measurable disease and a median progression-free survival of 5.7 months.6 Cabazitaxel and targeted therapy–based combinations will be attractive for future clinical trial testing.
Immune checkpoint therapies have taken the oncology world by storm, and advanced prostate cancer is no exception. Metastatic prostate cancer was the first malignancy within solid tumors to show an OS benefit in a placebo-controlled randomized trial with immunotherapy (sipuleucel-T).7 However, the advent of other, easy-to-use, effective therapies and the extraordinarily cumbersome nature of sipuleucel-T have been major hurdles in wide clinical application of the agent.
The synergy between the CTLA-4 inhibitor ipilimumab and radiation therapy was explored in mCRPC and showed preliminary promise, but it revealed a disappointing lack of OS benefit in a phase III trial. KEYNOTE-028 was a phase IB trial of the PD-L1 inhibitor pembrolizumab as a single agent in patients with pretreated mCRPC. Of 245 patients, 35 (14.3%) were PD-L1 positive, and 20 patients who were response evaluable were treated. Objective response rate was noted in five patients, with a median response duration of 58.7 weeks.8
Immune checkpoint blockade with the addition of pembrolizumab in patients with enzalutamide-resistant disease demonstrated promising efficacy, with three of the first 10 treated patients demonstrating a response with a PSA decline and decrease in size of measurable target lesions. Two responders who had tissue available were positive for PD-L1 expression, and one demonstrated microsatellite instability.9 A randomized trial of enzalutamide with or without atezolizumab is planned, and a combination of radium-223 and atezolizumab is currently in phase I testing in patients with mCRPC with measurable disease.
The vaccine-based immunotherapy strategy has a promising trajectory, especially if given in combination with immune modulators. The intriguing OS benefit shown by the phase II randomized trial of rilimogene galvacirepvec/rilimogene glafolivec (median OS of 25.1 months in the vaccine arm and 16.6 months in the placebo arm; HR 0.56; p = 0.0061) has heightened the interest in the awaited results of the phase III placebo-controlled trial. The ease of administration, tolerability, and the possibility of prolonged durable remissions are the biggest assets of vaccines. Although immunotherapy may hold the key to inducing durable remissions in mCRPC, it cannot be relied on for rapid control of symptomatic disease, and, clearly, combinations of agents will be required for optimal responses.
A phase I trial of a sequential combination of multipronged immune modulators, such as adenoviral vector vaccine (electroporated administration); tremelimumab, a CTLA-4 inhibitor; and myeloid-derived suppressor cell inhibition with sunitinib maintenance, is in progress (NCT02616185). The cellular immunotherapy development mainly consists of armed, activated T cells, which demonstrated safety and preliminary proof-of-principle activity. A phase II trial of bispecific antibody-armed activated T cells in combination with the PD-L1 inhibitor pembrolizumab is planned in mCRPC after our initial phase I trial that demonstrated safety and preliminary efficacy.10
Robinson et al. reported on genomic testing of the biopsy results of 150 patients with mCRPC and found that approximately 89% had actionable mutations, including 62% in the AR gene and 8% with actionable germline mutations.11 The frequency of DNA repair mutations (BRCA and ATM) was 19.3%.
The proportion of patients being enrolled on clinical trials of matched targeted therapies is rapidly expanding and will soon provide results of the impact of specific targeted therapies in mCRPC. PARP inhibitors have already demonstrated a large magnitude of durable response rates in mCRPC with DNA repair mutations.12 The promising efficacy resulted in the breakthrough designation of olaparib by the U.S. Food and Drug Administration in BRCA1/2 or ATM gene mutation–positive prostate cancer. Clinical trial evaluation of a number of other PARP inhibitors, such as rucaparib and niraparib, is ongoing.
PTEN loss (present in approximately 14% of prostate cancers tested) in advanced prostate cancer signifies unchecked activity of the mTOR and PI3K pathways. PI3K mutations are reported in approximately 27% of prostate cancer cases.13 Inhibitors of the PI3K pathway are in ongoing clinical trials, especially in patients with PTEN loss or ARAT-resistant disease. The IGF-1 receptor is another target that has been evaluated in clinical trials but has yielded disappointing clinical results.13 mTOR inhibition has been explored in mCRPC and has demonstrated modest clinical efficacy at best.14 The BET-1 inhibition pathway is also under active clinical investigation.15
Contemporary Management of mCRPC
Multiple decision dilemmas persist regarding management decisions and therapeutic sequencing in prostate cancer (Figure). The questions regarding which therapy to start and the odds of it actually helping or improving the life expectancy of a patient who is symptomatic are important and must be discussed in detail with the patient and their family.
Although median survival in mCRPC has nearly doubled in the past 10 years, and we have achieved the goal of less toxicity from therapies, there is work to be done in the optimization of systemic therapies. Early risk stratification and genomic characterization of tumors will help create plans of attack. DNA repair mutations, PI3K mutations, or PTEN loss can be identified before starting hormone agents, and then proactive planning for targeted therapies, such as PARP inhibitors or PI3K inhibitor–based clinical trials, can begin. If AR-V7 is identified, then early use of chemotherapy or clinical trials with N-terminal domain–inhibiting agents should be planned and discussed.
At present, we are using therapies and hoping that they curb disease progression for the patient’s lifetime. But a far-reaching, global, comprehensive therapeutic plan should be considered, and patients and their oncology care team should be having candid discussions about the various treatments and their sequence and utilization. We owe it to our patients to not limit our research to only developing novel agents, but also to be creative in optimizing outcomes from existing therapies.
About the Author: Dr. Vaishampayan is a professor of oncology at Wayne State University/Barbara Ann Karmanos Cancer Institute.