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Subjects:
Oncology
Prostate cancer is the most common tumor in men. Although there have been many new developments in the last few years, metastatic castration resistant prostate cancer remains a deadly disease.
- prostate cancer
- ADT
- PSMA Bite
1. Introduction
Prostate cancer is the most common solid cancer in men worldwide. The number of estimated new prostate cancers in the US in 2022 was 268,490. The number of estimated deaths due to prostate cancer is 34,500 [1]. Surgery and radiotherapy are the mainstay of treatment in localized disease. Androgen-deprivation-therapy (ADT), androgen signaling inhibition (ARSI) and chemotherapy dominate the standard medical treatment in recurrent or metastatic disease. However, the majority of patients acquire castration-resistance, which is associated with a poor prognosis.
The latest advancements in systemic treatments were the addition of Poly ADP-Ribose Polymerase Inhibitor (PARPi) and radio-ligand therapies (RLT) to the armentarium. While check point inhibitors (CPI) have revolutionized anti-cancer treatment in many diseases they were less successful in prostate cancer. A major driver of this immune resistance is derived from the dominance of a non-inflamed “cold” tumor environment in prostate cancer [2]. However, some activity has been noted for ipilimumab in men with mCRPC who were treated with at least one chemotherapy and had evidence of progression after the discontinuation of ADT [3], as well as for pembrolizumab in a subgroup of genetically instable prostate cancer patients [4].
Novel concepts are needed to advance immunotherapies in prostate cancer. Sipuleucel-T indicated that T-cell-based therapies were clinically active in principle and have led to further clinical development. Bispecific T Cell engager is a novel promising anti-cancer treatment modality in non-inflamed cancers, such as prostate cancer. These compounds re-direct T-cells to the tumor environment by targeting a cancer-specific epitope, such as PSMA in prostate cancer, which is linked to a component of the T-cell receptor (TCR). This mechanism recruits T-cells to the tumor milieu by binding to prostate cancer cells, which activates T-cells and enables immunologic anti-tumor response.
2. Current Treatment Options in Metastatic Prostate Cancer
2.1. Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)
2.1.1. Prognostic Factors
Several criteria have been established to estimate the prognosis of metastatic hormone-sensitive prostate cancer. Most common criteria are CHAARTED and LATITUDE criteria. These are summarized in Table 1 and Table 2.
Table 1. CHAARTED criteria [5].
| High Volume | Low Volume |
|---|---|
| At least 4 bone metastases - Including at least 1 outside vertebral column or pelvis or visceral metastasis |
High volume criteria not met |
Table 2. LATITUDE Criteria [6].
| High Risk | Low Risk |
|---|---|
| At least 2 risk factors of: - At least 3 bone metastasis - Visceral metastasis - ISUP 4 or higher |
High risk criteria not met |
The occurrence of “de novo” metastatic hormone-sensitive disease at the time of initial diagnosis was identified as a poor prognostic factor. The median overall survival (OS) was 51.6 months in low volume disease (HR = 1.64; 95% CI 1.16–2.31) and 43.2 months in high volume disease (HR = 2.48, 95% CI 1.83–3.36) compared to the reference group (prior local treatment/low volume disease HR = 1). These results differed substantially from those patients who had local therapy prior to the diagnosis of metastatic disease, i.e., metachronous metastatic prostate cancer. In this population, OS in low volume disease was 92.4 months (HR = 1) and 55.2 months in high volume disease (HR = 1.9, 95% CI 1.31–2.75 [7].
2.1.2. ADT
ADT is the standard treatment approach in mHSPC patients and may consist of Luteinizing hormone-releasing hormone (LHRH) agonists, LHRH antagonists or bilateral orchiectomy. In previous decades, ADT resided as single modality, but this is not the standard of care (SOC) anymore. OS in mHSPC patients treated with ADT alone is about 42 months [8].
Today, therapies that combine ADT with ARSI, chemotherapy, or both, yielded superior OS results. Single agent ADT has limited value and remains an option in elderly, frail patients, only.
2.1.3. Combination Therapies
The advent of combination therapies has intensified medical treatment and improved OS prognosis in prostate cancer patients with mHSPC. Different components were added to the ADT backbone.
An early set of treatment intensification trials tested the combination of ADT + docetaxel. There were two important trials, which investigated the combination of ADT and Docetaxel.
The STAMPEDE trial included patients with newly diagnosed M1 or N+ disease, locally advanced disease (cT3, cT4, ISUP grade at least 4, PSA at least 40 ng/mL) and patients with relapse after local treatment (PSA at least 4 ng/mL or PSA doubling time under 6 months or PSA level over 20 ng/mL, M or N relapse). In all, 689/724 (95%) of patients in the control arm and 347/362 patients in the Docetaxel arm had no previous treatment. A total of 1184 patients received the standard of care (ADT) and 592 patients received ADT + docetaxel. The median OS in the ADT group was 43.1 months, the estimated 5-year OS was 37% (CI 34–41%). In contrast, the median OS in patients who received ADT + Docetaxel was 59.1 months, the estimated 5-year OS was 49% (p = 0.003, HR = 0.81, 95% CI 0.69–0.95) [9].
The second Important trial was called CHAARTED, which also investigated the impact of ADT + docetaxel in patients with mHSPC and ECOG performance score 0–2. A distinction was made between high volume and low volume disease. In the overall patient population, OS was 57.6 months in the ADT + docetaxel group in contrast to 47.2 months in the ADT alone group (HR = 0.72, 95% CI 0.59 to 0.89; p = 0.0018). Subgroups of patients with high and low volume disease achieved different treatment effects. While ADT + docetaxel vs. ADT achieved a superior OS of 51.2 vs. 34.4 months (HR = 0.63, 95% CI 0.50 to 0.79; p < 0.001) in high volume disease, there was no benefit in patients with low volume disease in longterm follow-up (HR = 1.04, 95% CI 0.70 to 1.55; p = 0.86) [10].
As a result, OS in newly diagnosed metastatic hormone-sensitive prostate cancer is superior for ADT + docetaxel than ADT alone, but that effect of chemotherapy is restricted to high volume disease only.
2.1.4. ADT + Androgen Receptor Signaling Inhibitors (ARSI)
Abiraterone Acetate: Selective Inhibitor of Steroid 17α-Hydroxylase (CYP17A1)
In this section, we will discuss the impact of three different androgen receptor signaling inhibitors in addition to ADT.
The STAMPEDE trial also investigated the impact of Abiraterone Acetate (AA), a selective inhibitor of the enzyme steroid 17α-hydroxylase (CYP17A1) and prednisone in addition to ADT. Inclusion criteria were already mentioned above. In all, 957 received ADT alone, 960 patients were treated with ADT and Abiratrone Acetate + prednisone (AAP). There was a significant benefit in OS (HR = 0.63, 95% CI 0.52 to 0.76; p < 0.001) in patients who received the combination therapy which corresponded to 3-year OS rates 83% vs. 76%. Metastatic status at time of randomization had no significant impact on treatment effect (p = 0.37) [11].
In the LATITUDE trial, ADT + Placebo (n = 597 pts.) was compared to ADT + AAP (n = 602 pts.). Only patients with high-risk newly diagnosed metastatic disease, ISUP grade > 4, at least three bone lesions or measurable visceral metastases were included. The combination of ADT + AAP reported significant OS improvement (HR = 0.62, 95% CI 0.51–0.76; p < 0.001) when compared to ADT alone. Three year OS rates were: 66% in ADT + AAP vs. 49% in ADT + Placebo group [6].
In summary, the combination therapy of ADT + AAP provided a significant survival benefit over ADT monotherapy.
Enzalutamide: A Competitive Androgen Receptor Blocker
The ENZAMET trial included mHSPC patients (with distant metastases (M1) and ECOG score 0–2). 1125 men (588 with high volume disease, 537 with low volume disease) were 1:1 randomized to receive enzalutamide + ADT or ADT + standard nonsteroidal antiandrogen drug (bicalutamide, nilutamide, flutamide). Overall survival favored ADT + enzalutamide (HR = 0.67, 95% CI 0.52–0.86; p = 0.002) and 3 year OS rate were 80% in the Enzalutamide group and 72% for ADT alone. Regarding the volume of disease, the proportion alive after 36 months was 0.82 (0.75 to 0.87) in the control group vs. 0.90 (0.84 to 0.93) in the Enzalutamide group and low volume disease. In high volume disease, proportion alive after 36 months was 0.64 (0.58 to 0.70) in the control group and 0.71 (0.64 to 0.76) in the Enzalutamide group. There was no statistically significant impact of volume of disease (p = 0.14) [12].
Apalutamide: Inhibitor of the Ligand-Binding Domain of the Androgen Receptor
In the TITAN study, apalutamide + ADT (n = 525) was compared to ADT + Placebo (n = 527) in patients with mHSPC. A total of 94 of 525 patients in the Apalutamide group and 79 of 527 in the placebo group had previous treatment for localized disease. The other patients were de novo metastasized. The study reported superior OS in favor for the combination arm (HR = 0.67, 95% CI 0.51–0.89; p = 0.005). After 24 months, there was an overall survival of 82.4% in the Apalutamide group, but only 73.5% OS in the Placebo group [13] In the final analysis after 405 deaths, it was shown that apalutamide decreased the risk of death by 35% (HR = 0.65; 95% CI, 0.53 to 0.79; p < 0.0001) [14].
The results of these trials indicated that the combination therapy of ADT and ARSI improved OS in mHSPC patients than ADT alone. Both patient groups, high volume disease and low volume disease had a benefit from combination therapy.
2.1.5. Triple Combinations (ADT + ARSI + Docetaxel)
In this section, triple combinations in the treatment of mHSPC will be discussed.
Darolutamide is a competitive androgen receptor inhibitor and reported improved metastasis free survival and overall survival in non-metastatic CRPC patients. The principal activity paved the way for further testing in an earlier setting. The ARASENS trial investigated the combination of darolutamide + ADT + docetaxel (n = 651) compared to placebo + ADT + docetaxel (n = 655). The primary analysis at first data cut-off showed that the risk of death was reduced by 32.5% in the triple-therapy arm when compared to the ADT + docetaxel doublet [15].
PEACE-1 is a complex study and consisted of four arms. At this point, only the combination therapy of ADT + docetaxel with or without abiraterone acetate and prednisone (AAP) were considered for analyses. The median rPFS was prolonged by 2.5 years in patients who received the AAP containing triplet (HR = 0.5, 95% CI 0.40–0.62; p < 0.0001). Furthermore, there was a 25% reduction in the risk of death in patients who received the triplet (HR = 0.75, 95% CI 0.59–0.95); p = 0.017). The addition of Abiraterone improved the median OS from 4.72 years (SOC) to 5.72 years (SOC+abiraterone) (HR = 0.82, 95% CI 0.69–0.98; p = 0.030). Regarding patients with high tumor volume, there was a median survival benefit of 1.5 years in patients who were treated with the triplet (HR = 0.72, 95% CI 0.55–0.95; p = 0.019) [16].
As a result, triple therapies show a promising survival benefit in mHSPC patients, especially in those with high tumor burden. There are no comparisons between the triple and ADT + ARSI doublets available.
Table 3 provides a summary of the mentioned treatment options in mHSPC:
Table 3. List of treatment options and survival rates in mHSPC.
| Therapy | Trial Name | No. of Pts | Key Findings | Statistics |
|---|---|---|---|---|
| ADT | STAMPEDE (control arm) |
917 | Median OS: 43.1 months | IQR (22.7–90.7 months) |
| ADT + Docetaxel | STAMPEDE | SOC (ADT): 1184 pts. Docetaxel: 592 pts. |
43.1 months (SOC) 59.1 months (ADT + Docetaxel) |
HR = 0.81 p = 0.003 |
| ADT + Docetaxel | CHAARTED | SOC (ADT): 393 Docetaxel 397 |
SOC: 47.2 months ADT + Docetaxel 57.6 months |
HR = 0.72 p = 0.0018 |
| ADT + AAP | STAMPEDE | SOC (ADT): 957 ADT + AAP: 960 |
3 year OS: SOC: 76% ADT + AAP: 83% |
HR = 0.63 p < 0.001 |
| ADT + AAP | LATITUDE | ADT + Placebo: 597 ADT: AAP 602 |
3 year OS: SOC: 49% ADT + AAP: 66% |
HR = 0.62 p < 0.001 |
| ADT + Enzalutamide | ENZAMET | ADT + Bicalutamide/Nilutamide/Flutamide (SOC): 562 ADT: Enzalutamide 563 |
3 year OS: SOC: 72% ADT + Enzalutamide: 80% |
HR = 0.67 p = 0.002 |
| ADT + Apalutamide | TITAN | ADT + Placebo: 527 ADT + Apalutamide: 525 |
24 months OS: ADT + Placebo: 73.5% ADT + Apalutamide: 82.4% |
HR = 0.67 p = 0.005 |
| Darolutamide + ADT + Docetaxel | ARASENS | Darolutamide + ADT + Docetaxel: 651 Darolutamide + ADT + Placebo: 655 |
Risk of death 32.5% lower in Darolutamide group | HR = 0.68 p < 0.001 |
| Docetaxel + Abiraterone acetate/Prednisone + ADT | PEACE-1 | SOC: ADT 118; ADT + Docetaxel 178 ADT + Docetaxel + Abiraterone: 177 ADT + Abiraterone: 115 |
Median OS 4.72 years in SOC vs. 5.72 years (SOC + Abiraterone) 25% reduction in the risk of death AAP + ADT+ Docetaxel in pts. with high tumor burden: survial benefit of 1.5 years |
HR = 0.82 p = 0.030 HR = 0.75 p = 0.017 HR = 0.72 p = 0.019 |
2.2. Metastatic Castration Resistant Prostate Cancer (mCRPC)
2.2.1. Firstline Treatment in mCRPC
First-line treatment in men with mCRPC differ. Most trials explored the role of treatments after the failure of ADT alone.
Docetaxel was reported to improve OS compared to Mitoxantrone in the SWOG 99–16 trial. Docetaxel/Estramustine (every 3 weeks 60 mg/m2) was compared to Mitoxantrone and prednisone (every 3 weeks 12 mg/m2). Patients who received docetaxel had an overall survival of 17.5 months whereas patients who were treated with Mitoxantrone had an OS of only 15.6 months (p = 0.02; HR = 0.80; 95% CI 0.67–0.97). There was a significant difference in rPFS:6.3 months (Docetaxel) vs. 3.2 months (Mitoxantrone) (p < 0.001) [17].
The efficacy of abiraterone acetate before chemotherapy was shown in the placebo controlled COU-AA-302 trial. Patients who received abiraterone acetate + prednisone had superior OS than those in placebo + prednisone group (34.7 vs. 30.3 months HR 0.81, p = 0.0033). There was also a significant improvement in rPFS favoring AAP (16.5 months vs. 8.3 months; p < 0.0001) [18].
PREVAIL investigated the therapeutic benefit of enzalutamide in comparison to placebo in mCRPC in chemotherapy-naïve patients. Patients treated with enzalutamide had an OS of 32.4 months compared to 30.2 months in placebo group (HR = 0.71, 95% CI 0.60–0.84, p < 0.001). rPFS was significantly longer in patients who received enzalutamide (20.0 months vs. 5.4 months (HR = 0.186, 95% CI 0.15–0.23; p < 0.0001) [19].
The PROPEL trial investigated the combination of Olaparib + Abiraterone vs. Placebo + Abiraterone. This trial will be mentioned in detail in section “Molecular Therapies”.
Firstline options in CRPC are summarized in Table 4.
Table 4. Firstline options in CRPC.
| Therapy | Trial Name | Key Findings | Statistics |
|---|---|---|---|
| Docetaxel/Estramustine vs. Mitoxantrone | SWOG 99–16 | 17.5 mo (Docetaxel) vs. 15.6 mo. (Mitoxantrone) | p = 0.02 HR = 0.80 |
| Abiraterone+ Prendisolone vs. Prednisolone + Placebo | COU-AA-302 | 34.7 (AAP) vs. 30.2 months (Prednisolone + Placebo) | p = 0.0033 HR = 0.81 |
| Enzalutamide vs. Placebo | PREVAIL | OS 32.4 (Enzalutamide) vs. 30.2 mo | p < 0.001 |
2.2.2. Options after Pretreatment in mCRPC
For mCRPC patients who have already been treated with docetaxel, there are some therapeutic options, which will be listed below.
Cabazitaxel is a novel taxane with activity in docetaxel resistant CRPC. In the TROPIC 2013 trial, Cabazitaxel + prednisone showed a benefit in 2 year OS in comparison to mitoxantrone + prednisone (OS > 2 years in 15.9% (60/378) vs. 31/377 (8.2%). (odds ratio 2.11; 95% CI 1.33–3.33) [20].
The value of AAP in treatment of mHSPC has already been mentioned above. Additionally, in mCRPC it is a possible therapy option after docetaxel. In COU AA 301 study, AAP was compared to placebo/prednisone and led to an OS of 15.8 months in AAP group vs. 11.2 months in the placebo arm. (p < 0.0001, HR = 0.74, 95% CI: 0.64–0.86). Median rPFS was 5.6 months (5.6–6.5) in AAP group and 3.6 months (2.9–5.5) in control group (HR = 0.66, 0.58–0.76; p < 0·0001) [21].
Enzalutamide has been mentioned above. In the AFFIRM trial, patients who received enzalutamide after docetaxel had a significantly longer OS than those who received placebo (OS 18.4 vs. 13.6 months; (p < 0.001, HR = 0.63; 95% CI: 0.53–0.75)). There was also a statistically significant difference in rPFS: 8.3 months vs. 2.9 months (p < 0.001, HR = 0.63; 95% CI: 0.53–0.75) that favored enzalutamide [22].
In patients with two or more symptomatic bone metastases and no visceral metastases, alpharadin (Radium 223) is also a possible treatment option. Besides symptom relief in bone metastases, it also led to a longer OS in ALSYMPCA (Radium 223 vs. Placebo in previous or no previous docetaxel). OS in patients who received Radium 223 was 14.9 months vs. 11.3 months in placebo group (p = 0.002, HR = 0.61; 95% CI: 0.46–0.81) The most common hematologic AE in the Radium-223 group was anemia (187/600 pts.; 31%) whereas bone pain (300/600 pts.; 50%) and nausea (213/600 pts.; 36%) where most common nonhematologic AEs. [23].
In the CARD study, Cabazitaxel was compared to Abiraterone or Enzalutamide in patients with mCRPC who were treated with Doxetaxel and Abiraterone or Ezalutamide. In all, 255 patients were randomized in two groups: one group received Cabazitaxel (129 pts.), the other group received Abiraterone or Enzalutamide depending on which they had not received yet (126 pts.). The median overall survival was 13.6 months in the Cabazitaxel group and 11.0 months in the Abiraterone/Enzalutamide group (HR for death = 0.64; 95% CI, 0.46 to 0.89; p = 0.008). The median progression-free survival was 4.4 months in Cabazitaxel group vs. 2.7 months in the other group. (HR for progression or death =0.52; 95% CI, 0.40 to 0.68; p < 0.001). As a result, Cabazitaxel resulted in longer overall survival and progression-free survival [24].
Options after pretreatment are summarized in Table 5.
Table 5. Options after pretreatment in mCRPC.
| Treatment | Pre-Therapy, Main Inclusion Criteria | Trial | Main Result | Statistics |
|---|---|---|---|---|
| Cabazitaxel + Prednisolone vs. Mitoxantrone + Prednisolone | Docetaxel | TROPIC 2013 | 2 year OS 15.9% (Cabazitaxel) vs. 8.2% (Mitoxantrone). | Odds ratio 2.11 95% CI 1.33–3.33 |
| Abiraterone Acetate + Predni vs. Placebo + Predni | Docetaxel | COUAA301 | OS 15.8 (Abiraterone) vs. 11.2 mo. | p < 0.0001 HR = 0.74 |
| Enzalutamide vs. Placebo | Docetaxel | AFFIRM 2012 | OS 18.4 (Enzalutamide) vs. 13.6 mo. | p < 0.001 HR = 0.63 |
| Cabazitaxel vs. Abiraterone or Enzalutamide | Docetaxel and Abiraterone or Enzalutamide | CARD | OS 13.6 (Cabazitaxel) vs. 11.0 mo. | p = 0.008 HR = 0.64 |
| Radium 223 vs. Placebo | Previous or no previous docetaxel Two or more symptomatic bone mts. No visceral mts. |
ALSYMPCA 2013 | OS 14.9 (Radium 223) vs. 11.3 mo. | p = 0.002 HR = 0.61 |
This entry is adapted from the peer-reviewed paper 10.3390/cancers15020461
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