Despite the introduction of novel therapies over the past decade, advanced prostate cancer remains an incurable disease in need of new strategies to overcome drug resistance.
Despite the introduction of novel therapies over the past decade, advanced prostate cancer remains an incurable disease in need of new strategies to overcome drug resistance. Investigators are exploring many approaches, including more potent antiandrogen agents, immune checkpoint immunotherapies, and molecularly targeted drugs (Figure1,2).
Androgen deprivation therapy (ADT) remains the backbone of treatment for advanced tumors, but patients will invariably relapse and transition to a particularly challenging castration-resistant state.3 Consequently, prostate cancer is the second-leading cause of cancer-related mortality among men in the United States.4
An improved understanding of the mechanisms underlying prostate cancer has led to the development of a new generation of androgen receptor (AR) antagonists being introduced earlier in the treatment timeline. Over the past 18 months, the FDA has approved apalutamide (Erleada) and darolutamide (Nubeqa) for patients with nonmetastatic castration-resistant prostate cancer (CRPC).5,6
Meanwhile, immunotherapies aimed at the PD-1/PD-L1 pathway and small molecules targeting PARP are among many targets in development, according to information on the ClinicalTrials.gov website (Table).
Although efforts to target the PI3K pathway and to cash in on the success of immunotherapy in other tumor types have resulted in some disappointment, ongoing research into combination strategies and potential biomarkers of response is generating promising signals.
Androgens in the Driver's Seat
Prostate cancer has long been recognized as a hormonally driven disease. Nobel Prizewinning research conducted in the 1940s heralded the introduction of ADT,3 the goal of which is to reduce circulating levels of androgens, consisting predominantly of testosterone and its derivative, 5-dihydrotestosterone, to curb prostate cancer growth.7
Androgens are essential for the development and normal function of the prostate. They bind to the AR in the cytoplasm of target cells, releasing the receptor from an inactive protein complex and allowing it to move into the nucleus, where it orchestrates cellular effects by binding to androgen-responsive elements, inducing transcription of target genes.8,9 Many of these target genes are involved in the growth and survival of prostate cancer cells, and aberrant activation of AR signaling has been strongly implicated in the development of prostate cancer.10
ADT is achieved either surgically, through removal of the testes, or chemically, through the use of drugs that block the activity of luteinizing hormone-releasing hormone (LHRH), which stimulates production of testosterone by the testes. Because other parts of the body can produce testosterone, neither surgical nor chemical castration completely eliminates androgens.3,7
This obstacle prompted the development of antiandrogens, drugs designed to block the body’s ability to use androgens by inhibiting the activity of the AR. The first nonsteroidal antiandrogens—bicalutamide, nilutamide, and flutamide—were effective at achieving maximal AR blockade but did not prevent development of CRPC.3,7,11
Intensive research efforts have uncovered at least 3 major mechanisms of castration resistance: bypass signaling, in which cells develop mechanisms to evade AR blockade, through, for example, upregulation of the closely related glucocorticoid receptor; changing phenotype, which involves dedifferentiation into a neuroendocrine form of prostate cancer; and reactivation of AR signaling, which can be achieved in many ways, including via AR gene amplification, AR protein overexpression, mutations in the AR ligand-binding domain, and AR splice variants.12
By leveraging a greater understanding of CRPC biology, investigators developed enzalutamide (Xtandi), a second-generation, more potent AR antagonist. The FDA first approved the drug in 2012 for patients with metastatic CRPC (mCRPC) previously treated with docetaxel. The agency recently expanded the approval to include all patients with CRPC, even nonmetastatic cases, based on the results of the PROSPER trial, which demonstrated a statistically significant improvement in metastasis-free survival (MFS) compared with placebo (36.6 vs 14.7 months, respectively; HR, 0.29; P <.0001).13
An alternative means of indirectly inhibiting the AR pathway is to target the 17α-hydroxylase/C17,20-lyase enzyme, which plays a critical role in androgen synthesis.14 One agent with this mode of action is abiraterone acetate (Zytiga), which was approved in combination with prednisone in 2011 for patients with mCRPC previously treated with docetaxel. Subsequently, abiraterone was approved in 2012 for all patients with mCRPC, regardless of prior chemotherapy.15
Investigators are studying both abiraterone and enzalutamide beyond the setting of castration-resistant disease. Abiraterone was approved in February 2018 for use in metastatic, castration-sensitive prostate cancer based on findings from the LATITUDE trial, in which the drug improved overall survival (OS) when used in combination with ADT (HR, 0.62; P <.0001).15
Investigators are evaluating enzalutamide in the phase III ENZAMET trial in the metastatic hormone-sensitive setting. At 3 years, 80% of patients treated with enzalutamide were still alive compared with 72% of patients treated with a first-generation antiandrogen, translating into a 33% reduction in the risk of death (HR, 067; P = .002), according to an interim analysis presented at the 2019 American Society of Clinical Oncology Annual Meeting (ASCO 2019).16
Both drugs are also being examined in patients with localized disease.
In addition, a number of more potent AR antagonists have been developed with reduced central nervous system distribution in the hopes of reducing adverse effects (AEs).17 Two such agents, apalutamide and darolutamide, were both approved in nonmetastatic settings.
Apalutamide was approved on the basis of findings from the phase III SPARTAN trial, in which 1207 patients received apalutamide 240 mg once daily or placebo, in combination with an LHRH analogue or following bilateral orchiectomy. The median MFS was 40.5 months in the apalutamide arm compared with 16.2 months for placebo (HR, 0.28; P <.0001).18
Apalutamide has also demonstrated promising efficacy in patients with metastatic castration-sensitive disease, and the FDA is reviewing a supplemental new drug application in this setting.19 The results of the phase III TITAN trial demonstrated improved 2-year radiographic progression-free survival (rPFS; 68.2% vs 47.5%; HR, 0.48; P <.001) and OS (82.4% vs 73.5%; HR, 0.67; P = .005) for apalutamide compared with placebo.20
Darolutamide is even more potent than apalutamide; it is unique in that it is not affected by the AR F876L mutation or other well-known mutations shown to confer castration resistance.11 Approval was based on the results of the phase III ARAMIS trial. Among 1509 patients randomly assigned to darolutamide 600 mg twice daily or placebo, the median MFS was 40.4 months for darolutamide and 18.4 months for placebo (HR, 0.41; P <.0001).17
Proxalutamide, another AR antagonist, is among several agents currently in early-stage clinical testing. Other novel drugs in this class include AZD5312, an antisense oligonucleotide targeting AR messenger RNA, and ARV-110, a targeted degrader of the AR. The latter exploits the ubiquitin-proteasome system, tagging the AR for degradation by the proteasome, and was granted fast track designation in May 2019 for the treatment of mCRPC.21
A "Hot" Target for Immunotherapy
Beyond chemotherapy and antiandrogens, the only other approved drug for the treatment of advanced prostate cancer is sipuleucel-T (Provenge), a therapeutic cancer vaccine that has been on the market since 2010.22 Owing to a number of issues, sipuleucel-T has not been widely adopted in clinical practice, but it opened the door for immunotherapy in prostate cancer.22
Unfortunately, immunotherapy has not yet enjoyed the same level of success in prostate cancer as it has in other tumor types. The use of therapeutic vaccines is an area of ongoing clinical research. Unlike prophylactic vaccines, which are used in disease prevention, therapeutic vaccines are designed to exploit tumor-specific antigens to boost the immune response to treat disease that is already established. However, the most promising agent, PROSTVAC, a vector-based vaccine targeting prostate-specific antigen (PSA), afforded no survival benefit in a phase III study.
Although tumor-infiltrating T cells that express PD-1 and one of its ligands, PD-L1, have been observed in prostate cancer, clinical trials of immune checkpoint inhibitors (ICIs) have also proved underwhelming.23
The tumor-agnostic approval of pembrolizumab (Keytruda), a PD-1 inhibitor, in patients with solid tumors exhibiting high levels of microsatellite instability (MSI) means this drug is available for the treatment of MSI-high prostate cancers. However, this group represents only 3% of patients, according to one study.24,25
Defects in DNA repair genes lead to the MSI-high phenotype, which is associated with increased mutational burden. Investigators believe that a higher mutational burden provides greater numbers of neoantigens to stimulate an antitumor immune response, rendering a tumor immunologically “hot” and boosting response to immunotherapy.26
Investigators have recently exploited this hypothesis by testing rational drug combinations designed to turn immunologically “cold” tumors into “hot” ones, a strategy making some headway in prostate cancer. A particular focus is on the combination of ICIs with AR-targeting drugs or focused use of ICI monotherapy in patients previously treated with AR-targeting drugs.
At the 2019 Genitourinary Cancers Symposium, investigators presented results from a cohort of patients in the KEYNOTE-365 trial who had abiraterone-pretreated mCRPC and had received pembrolizumab and enzalutamide. The objective response rate was 20%, with 2 complete responses and 3 partial responses (PRs).27
Evidence Builds for Inhibiting PARP
Defective DNA repair promotes carcinogenesis by fostering underlying genomic instability and is a recognized hallmark of cancer. A greater understanding of the molecular components and pathways of DNA repair has enabled development of drugs designed to exploit them.
The most renowned drugs in this space are the PARP inhibitors, which have proved highly effective in the treatment of patients with ovarian and breast cancers, particularly those who have mutations in the breast cancer susceptibility genes BRCA1 and BRCA2.
BRCA proteins are involved in the repair of double-strand DNA breaks, whereas PARP proteins repair breaks in only a single strand; the 2 types of repair occur via distinct mechanisms. Tumors that already have DNA repair mechanism defects, such as BRCA1/2 mutations, are exquisitely sensitive to PARP inhibition because it knocks out their backup repair pathways and renders them unable to repair damaged DNA, triggering cell death.28
DNA repair defects have been identified in up to one-fifth of patients with mCRPC.29 Germline BRCA2 mutations have been observed in patients with prostate cancer, and although the overall prevalence is low, they confer the highest risk of prostate cancer of any heritable gene mutation identified to date. Defective DNA repair may also have a prognostic value in prostate cancer, conveying worse outcomes and more aggressive disease.30-32
In 2015, the results of the TOPARP-A trial generated great excitement over the potential of PARP inhibitors in patients with mCRPC, and in January 2016 the FDA granted olaparib (Lynparza) a breakthrough therapy designation for BRCA1/2- and ATM-mutated CRPC.
Most notably, results of the trial showed particularly impressive responses in patients with DNA repair defects (88% response rate).32,33 Subsequent trials of PARP inhibitors in unselected patient populations have proved disappointing, but exploratory analyses demonstrated the importance of using biomarkers to select patients for PARP inhibitor therapy.34
Subsequent studies in patients with DNA repair defects were more promising.
Investigators presented results from TOPARP-B, in which only patients with DNA repair defects were enrolled, at ASCO 2019. A total of 98 patients whose mCRPC progressed after taxane chemotherapy were randomized to receive 300 mg or 400 mg of olaparib twice daily. The response rate (a composite of radiologic response, PSA decline of ≥50%, and/or circulating tumor cell count conversion from ≥5 cells/7.5 mL blood to <5 cells/7.5 mL) was 39.1% and 54.3% in the 300-mg and 400-mg cohorts, respectively. Patients with BRCA1/2 mutations had the highest response rate, 83.3%.35
In the second-line setting, olaparib demonstrated a statistically significant improvement in rPFS versus enzalutamide or abiraterone in men with mCRPC with BRCA1/2 or ATM gene mutations in the phase III PROfound trial (NCT02987543). AstraZeneca and Merck, the companies jointly developing olaparib, announced these results in August 2019.36
The study sought to recruit 340 patients with mCRPC who had progressed on prior therapy with a new hormonal agent and harbored a mutation in 1 of 15 homologous recombination repair pathway genes. The primary endpoint was rPFS in participants with BRCA1/2 or ATM mutations. Full data are expected to be presented at an upcoming medical meeting.36
Investigators also recently presented results from an ongoing phase II trial of niraparib (Zejula), which enrolled patients with DNA repair defects. In an analysis of 39 patients with confirmed biallelic defects in DNA repair genes treated at a dose of 300 mg/day, niraparib achieved a composite response rate of 65% and an objective response rate of 38% in 23 patients with BRCA1/2 mutations.37 Phase III clinical trials of these and 2 other PARP inhibitors are ongoing in mCRPC.
In addition, investigators are studying combination therapy with PARP inhibitors, with AR pathway inhibitors and ICIs demonstrating particular promise. The combination of olaparib and abiraterone was recently evaluated in a phase II trial. Among 142 patients, median rPFS was 13.8 months for patients treated with the combination compared with 8.2 months for those treated with abiraterone and placebo (HR, 0.65; P = .034).38
Meanwhile, the KEYNOTE-365 trial evaluated the combination of olaparib and pembrolizumab in cohort A: patients (n = 41) who had previously been treated with chemotherapy and up to 2 hormonal therapies. The composite response rate was 15%; objective response rate was 7%, including 2 PRs; and PSA response was 13%.39
PI3K Pathway Disappointment
Along with the AR pathway, the PI3K pathway is one of the most frequently activated cell signaling networks in prostate cancer; alterations in components of this pathway are found in almost all patients with CRPC.12
A range of drugs have been developed to block PI3K pathway activity. Pan-PI3K inhibitors and isoform-specific PI3K inhibitors have shown limited activity owing to a combination of dose-limiting toxicities, inadequate target inhibition, and upregulation of compensatory pathways. Drugs targeting other components of the pathway, including AKT and mTOR, have also failed to progress.12,40-43
Although clinical trials of PI3K pathwaytargeting drugs continue, particularly AKT and PI3Kβ inhibitors, the focus has more recently shifted to combination therapy in recognition of the substantial cross-talk between the PI3K and AR pathways. Cross-talk could be a major limiting factor in the efficacy of PI3K inhibitors tested to date.12
A recent phase II study of the AKT inhibitor ipatasertib (200 mg or 400 mg) in combination with abiraterone demonstrated a trend toward superiority for the combination over abiraterone plus placebo in terms of rPFS. The median rPFS with the combination was 8.31 months at 200 mg and 8.18 months at 400 mg versus 6.37 months for the placebo arm (HR, 0.94 and 0.75, respectively; P = .75 and .17, respectively). The trend was particularly pronounced among patients with loss of the tumor suppressor protien PTEN, as determined by immunohistochemical analysis.44
Other PI3K—AR inhibitor combinations have not proved as successful, which has led to suggestions that biomarkers of response may hold the key to effective use of PI3K pathway inhibitors in prostate cancer.45,46 In the above study, the ipatasertib/abiraterone combination was particularly effective in tumors with loss of the PTEN gene, which encodes a phosphatase that counteracts the activity of the PI3K pathway.44
Prostate-specific membrane antigen (PSMA), a membrane-bound protein highly expressed on prostate cancer cells, is another emerging target in this field. PSMA-targeted antibodies and small molecule inhibitors conjugated to radioactive isotopes have revolutionized prostate cancer imaging and are now also being repurposed as therapeutics.2 The most clinically advanced agent is 177Lu-PSMA-617, which investigators are evaluating in the phase III VISION trial (NCT03511664).
Other strategies focus on novel methods of overcoming mechanisms of castration resistance, including the development of glucocorticoid receptor antagonists, because upregulation of this receptor has been shown to be a common mechanism of resistance to antiandrogen therapy.47
Findings from a recent study evaluating resistance mechanisms in patients treated with AR-targeted drugs uncovered an increasingly common type of prostate tumor that neither reactivates the AR pathway nor undergoes differentiation to a neuroendocrine (NE) phenotype. The investigators dubbed these AR-null/NE-null tumors “double-negative” prostate cancer. In trying to uncover the molecular changes that allow this tumor type to survive and grow in the absence of AR signaling, they discovered that the fibroblast growth factor receptor (FGFR) and MAPK pathways were overactivated, suggesting that agents targeting these pathways might be particularly efficacious in AR-null mCRPC. Trials of FGFR inhibitors have had limited efficacy to date in patients with mCRPC unselected for loss of AR activity. 48 However, an ongoing trial specifically enrolling patients with double-negative tumors (NCT03999515) will evaluate the FGFR antagonist erdafitinib (Balversa) combined with ADT in a population predicted to respond well to such a combination.